Electric Field-Based Cancer Therapy Induces the Expression of HMGB1 and PD-L1 mRNA Genes on Breast Tumor of Female Rats

Siti Fathurrohmah, G.A.B Yehezkiel P. Cahyadi, Firman Alamsyah, Rarastoeti Pratiwi

Abstract


Electro Capacitive Cancer Therapy (ECCT) is an electric field-based cancer therapy method using intermediate frequency (150 kHz) and low intensity (18 Vpp). High Mobility Group Box 1 (HMGB1) is a cytokine related to damage-associated molecular patterns (DAMPs) secreted by dead cells. The expression of Programmed Death Ligand 1 (PD-L1) is ligand present on the surface of tumor cells and its expression is associated with the increase in the number CD8+ T lymphocytes. This study aims to examine the effect of ECCT exposure on the expression of HMGB1 and PD-L1 genes on the breast tumor, brain, and liver tissues of Rattus norvegicus (Berkenhout, 1769). The tissues were obtained from the previous studies stored in RNAlater (-20˚C). Female rat tissues of the previous study from four treatment groups, namely the control group (NINT), non-DMBA-induction with therapy (NIT), DMBA-induction with non-therapy (INT), and DMBA-induction with therapy (IT). Gene expression was analyzed using the RT-qPCR. Statistical t-test with a p<0.05 significance level was performed using GraphPad Prism 9.4.0 software. The result shows HMGB1 and PD-L1 mRNA genes were both significantly expressed in breast tumor samples. The liver and brain samples of normal rats did not show any significant changes in the activity of these genes after exposure to the electric field. This study indicates that exposure to electric fields may trigger the expression of HMGB1 and PD-L on the rat’s breast tumor samples. This study also provides information related to the safety of ECCT in healthy organs of female rats, especially the brain and liver.


Keywords: ECCT, breast tumor, HMGB1, PD-L1, IFN- γ.


Full Text:

PDF

References


Alamsyah, F., Ajrina, I., Dewi, F., Iskandriati, D., Prabandari, S., and Taruno, W., 2015, Antiproliferative Effect of Electric Fields on Breast Tumor Cells In Vitro and In Vivo, Indonesian Journal of Cancer Chemoprevention., 6(3), 71-77. CrossRef

Apetoh, L., Ghiringhelli, F., Tesniere, A., Criollo, A., Ortiz, C., Lidereau, R., et al., 2007, The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy, Immunol Rev., 220(1), 47–59. CrossRef

Alamsyah, F., Pratiwi, R., Firdausi, N., Pello, J.I.M., Nugraheni, S.E., Fadhlurrahman, A.G., et al., 2021, Cytotoxic T cells response with decreased CD4/CD8 ratio during mammary tumors inhibition in rats induced by non-contact electric fields, F1000Research, 10, 35. CrossRef

Berzingi, S., Newman, M., and Yu, H.G., 2016, Altering bioelectricity on inhibition of human breast cancer cells, Cancer Cell Int, 16, 72. CrossRef

Castro, F., Cardoso, A.P., Gonçalves, R.M., Serre, K., and Oliveira, M.J., 2018, Interferon Gamma at the Crossroads of Tumor Immune Surveillance or Evasion, Frontiers in Immunology, 9, 847. CrossRef

Dai, C., and Krantz, S.B., 1999, Interferon gamma induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells, Blood, 93(10), 3309–3316. Link

Dong, H., Zhang, L., and Liu, S., 2022, Targeting HMGB1: An available Therapeutic Strategy for Breast Cancer Therapy, Int J Biol Sci., 18(8), 3421-3434. CrossRef

Garcia-Diaz, A., Shin, D.S., Moreno, B.H., Saco, J., Escuin-Ordinas, H., Rodriguez, G.A., et al., 2017, Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression, Cell Reports, 19(6), 1189–1201. CrossRef

Horras, C.J., Lamb, C.L., and Mitchell, K.A., 2011, Regulation of hepatocyte fate by interferon-γ, Cytokine and growth factor reviews, 22(1), 35–43. CrossRef

Gao, Q., Li, F., Wang, S., Shen, Z., Cheng, S., Ping, Y., et al., 2019, A cycle involving HMGB1, IFN-γ and dendritic cells plays a putative role in anti-tumor immunity, Cellular Immunology, 343, 103850. CrossRef

Hubert, P., Roncarati, P., Demoulin, S., Pilard, C., Ancion, M., Reynders, C., et al., 2021, Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy, Journal for immunotherapy of cancer, 9(3), e001966. CrossRef

Ibrahim, E.M., Al-Foheidi, M.E., Al-Mansour, M.M., and Kazkaz, G.A., 2014, The prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancer: A meta analysis, Breast Cancer Res. Treat., 148, 467–476. CrossRef

Kaplan, D.H., Shankaran, V., Dighe, A.S., Stockert, E., Aguet, M., Old, L.J., and Schreiber, R.D., 1998, Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice, Proceedings of the National Academy of Sciences of the United States of America, 95(13), 7556–7561. CrossRef

Kirson, E.D., Gurvich, Z., Schneiderman, R.D., Itzhaki, A., Wasserman, Y., Schatzberger, R., and Palti, Y., 2004, Disruption of cancer cell replication by alternating electric fields, Cancer Res., 64, 3288-3295. CrossRef

Krysko, D.V., Garg, A.D., Kaczmarek, A., Krysko, O., Agostinis, P., and Vandenabeele, P., 2012, Immunogenic cell death and DAMPs in cancer therapy, Nat Rev Cancer, 12, 860–875. CrossRef

Kythreotou, A., Siddique, A., Mauri, F.A., Bower, M., Pinato, D.J., 2018, PD-L1, Journal of Clinical Pathology, 71, 189-194. CrossRef

Lin, R., Cai, J., Kostuk, E.W., Rosenwasser, R., and Iacovitti, L., 2016, Fumarate modulates the immune/inflammatory response and rescues nerve cells and neurological function after stroke in rats, Journal of Neuroinflammation, 13(1), 269. CrossRef

Liu, X., Li, H., Xu, Q., Mei, L., Miao, J., Wen, Q., et al., 2019, Anti-Inflammatory Effects of Shenfu Injection against Acute Lung Injury through Inhibiting HMGB1-NF-κB Pathway in a Rat Model of Endotoxin Shock, Evidence-Based Complementary and Alternative Medicine, 2019, 9857683. Link

Lotfinejad P, Jafarabadi M.A., Shadbad, M.A., Kazemi, T., Pashazadeh, F., Shotorbani, S.S., et al., 2020, Prognostic Role and Clinical Significance of Tumor-Infiltrating Lymphocyte (TIL) and Programmed Death Ligand 1 (PD-L1) Expression in Triple-Negative Breast Cancer (TNBC): A Systematic Review and Meta-Analysis Study, Diagnostics, 10(9),704. CrossRef

Mujib, S.A., Alamsyah, F., and Taruno, W.P., 2017, Cell Death and Induced p53 Expression in Oral Cancer, HeLa, and Bone Marrow Mesenchyme Cells under the Exposure to Noncontact Electric Fields, Integrative Medicine International, 4, 161–170. CrossRef

Pratiwi, R., Antara, N.Y., Fadliansyah, L.G., Ardiansyah, S.A., Nurhidayat, L., Sholikhah, E.N., et al., 2020, CCL2 and IL18 expressions may associate with the anti-proliferative effect of noncontact electro capacitive cancer therapy in vivo, F1000Research, 8, 1770. CrossRef

Schalper, K.A., Velcheti, V., Carvajal, D., Wimberly, H., Brown, J., Pusztai, L., et al., 2014, In Situ Tumor PD-L1 mRNA Expression Is Associated with Increased TILs and Better Outcome in Breast Carcinomas, Clinical Cancer Research, 20(10), 2773-2782. CrossRef

Takaki, H., Hirata, Y., Ueshima, E., Kodama, H., Matsumoto, S., Wada, R., et al., 2020, Hepatic Arthery Embolization Enhances Expression of Programmed Cell Death 1 Ligand in an Orthotopic Rat Hepatocellular Carcinoma Model: In Vivo and in Vitro Experimentation, Journal of Vascular and Interventional Radiology, 31, 1475-1482.e2. CrossRef

Taki, F.A., Abdel-Rahman, A.A., and Zhang, B., 2014, A comprehensive approach to identify reliable reference gene candidates to investigate the link between alcoholism and endocrinology in Sprague-Dawley rats, PLoS One, 9(5), e94311. CrossRef

Wang, X., Teng, F., Kong, L., and Yu, J., 2016, PD-L1 expression in human cancers and its association with clinical outcomes, Onco Targets Ther., 12(9), 5023-5039. CrossRef

Wang, C., Ma, C., Gong, L., Guo, Y., Fu, K., Zhang, Y., et al., 2021, Macrophage Polarization and Its Role in Liver Disease, Frontiers in Immunology, 12, 1-25. CrossRef




DOI: http://dx.doi.org/10.14499/indonesianjcanchemoprev13iss2pp128-136

Copyright (c) 2022 Indonesian Journal of Cancer Chemoprevention

Indexed by:

                  

               

 

Indonesian Society for Cancer Chemoprevention