Reports of Biochemistry
and Molecular Biology
Tue, Oct 15, 2024
[Archive]
Volume 12, Issue 3 (Vol.12 No.3 Oct 2023)
rbmb.net 2023, 12(3): 403-414 |
Back to browse issues page
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Bahaa Eldeen N M, Kamel M M, Mohamed A, Kamar S S, Rashed L, Shams Eldeen A M. Melatonin Mitigates the Progression of Chemically Induced Hepatocellular Carcinoma in Rats via Targeting Wnt/Β-Catenin Pathway, and Small Noncoding miR-let-7b. rbmb.net 2023; 12 (3) :403-414
URL: http://rbmb.net/article-1-1284-en.html
URL: http://rbmb.net/article-1-1284-en.html
Nesma Mohammed Bahaa Eldeen 
, Moataz Maher Kamel , Abbas Mohamed , Samaa Samir Kamar , Laila Rashed , Asmaa Mohammed Shams Eldeen *
, Moataz Maher Kamel , Abbas Mohamed , Samaa Samir Kamar , Laila Rashed , Asmaa Mohammed Shams Eldeen *
Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt.
Abstract: (894 Views)
Background: Melatonin, the controlling hormone of the sleep–wake cycle, has acquired attention due to its role in immunomodulation, anti-inflammation, as well as its proapoptotic effects. Wnt/β-catenin signaling can modulate cancer progression by promoting cell division and migration, while miR-let-7b may inhibit cell growth, migration, and invasion by affecting the function of adaptive immune cells. This work was designed to detect the effect of using melatonin as an immunomodulating therapeutic approach to control the progression of chemically induced hepatocellular carcinoma (HCC).
Methods: Thirty male rats were equally divided into control, HCC, and melatonin-HCC groups. Animals in the HCC and melatonin-HCC groups were injected with diethylnitrosamine (intraperitoneal single dose) followed by repeated carbon-tetrachloride subcutaneous injection once weekly for six weeks. Melatonin was given from the first week of the study and continued during the process of HCC induction.
Results: In the HCC group, the levels of tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), and Wnt/β-catenin expression significantly increased, while there was a downregulation of microRNA Let7b. Melatonin administration reversed these changes, along with an increase in hepatic content of interleukin-2 (IL-2) and caspase-3.
Conclusions: Melatonin exerted hepatic immunomodulating changes, in addition to proapoptotic and antiangiogenic effects, illustrated by increased IL-2, caspase-3, and decreased VEGF levels, respectively. Moreover, the use of melatonin during hepatocarcinogenesis positively modulated the disrupted expression of microRNA let7b and Wnt/β-catenin significantly.
Methods: Thirty male rats were equally divided into control, HCC, and melatonin-HCC groups. Animals in the HCC and melatonin-HCC groups were injected with diethylnitrosamine (intraperitoneal single dose) followed by repeated carbon-tetrachloride subcutaneous injection once weekly for six weeks. Melatonin was given from the first week of the study and continued during the process of HCC induction.
Results: In the HCC group, the levels of tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), and Wnt/β-catenin expression significantly increased, while there was a downregulation of microRNA Let7b. Melatonin administration reversed these changes, along with an increase in hepatic content of interleukin-2 (IL-2) and caspase-3.
Conclusions: Melatonin exerted hepatic immunomodulating changes, in addition to proapoptotic and antiangiogenic effects, illustrated by increased IL-2, caspase-3, and decreased VEGF levels, respectively. Moreover, the use of melatonin during hepatocarcinogenesis positively modulated the disrupted expression of microRNA let7b and Wnt/β-catenin significantly.
Type of Article: Original Article |
Subject:
Immunology
Received: 2023/11/9 | Accepted: 2024/01/2 | Published: 2024/02/25
Received: 2023/11/9 | Accepted: 2024/01/2 | Published: 2024/02/25
References
1. Balogh J, Victor D 3rd, Asham EH, Burroughs SG, Boktour M, Saharia A, Li X, Ghobrial RM, Monsour HP Jr. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016;3:41-53. [DOI:10.2147/JHC.S61146] [PMID] []
2. Fortress A, Frick K. Hippocampal Wnt Signaling: Memory Regulation and Hormone Interactions. The Neuroscientist. 2016;22(3):278-294. [DOI:10.1177/1073858415574728] [PMID] []
3. Pai SG, Carneiro BA, Mota JM, Costa R, Leite CA, Barroso-Sousa R, et al. Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol. 2017;10(1):101. [DOI:10.1186/s13045-017-0471-6] [PMID] []
4. Duspara K, Bojanic K, Pejic JI, Kuna L, Kolaric TO, Nincevic V, et al. Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options. An Update. J Clin Transl Hepatol. 2021;9(6):960-971.
5. Gordon MD, Nusse R. Wnt signaling: Multiple pathways, multiple receptors, and multiple transcription factors. Journal of Biological chemistry. 2006;281(32):22429-33 [DOI:10.1074/jbc.R600015200] [PMID]
6. Chae WJ, Bothwell ALM. Canonical and Non-Canonical Wnt Signaling in Immune Cells. Trends Immunol. 2018;39(10):830-847. [DOI:10.1016/j.it.2018.08.006] [PMID] []
7. Monga SP. β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis. Gastroenterology. 2015;148(7):1294-310. [DOI:10.1053/j.gastro.2015.02.056] [PMID] []
8. Liao DJ, Thakur A, Wu J, Biliran H, Sarkar FH. Perspectives on c-Myc, Cyclin D1, and their interaction in cancer formation, progression, and response to chemotherapy. Crit Rev Oncog. 2007;13(2):93-158. [DOI:10.1615/CritRevOncog.v13.i2.10] [PMID]
9. Wang Y, Mo Y, Wang L, Su P, Xie Y. Let-7b contributes to hepatocellular cancer progression through Wnt/β-catenin signaling. Saudi J Biol Sci. 2018;25(5):953-958. [DOI:10.1016/j.sjbs.2018.03.004] [PMID] []
10. Chen F, Chen C, Yang S, Gong W, Wang Y, Cianflone K, et al. Let-7b inhibits human cancer phenotype by targeting cytochrome P450 epoxygenase 2J2. PLoS One. 2012;7(6):39197. [DOI:10.1371/journal.pone.0039197] [PMID] []
11. Akao Y, Nakagawa Y, Naoe T. let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol Pharm Bull. 2006;29:903-906. [DOI:10.1248/bpb.29.903] [PMID]
12. Carrillo-Vico A, Lardone PJ, Fernández-Santos JM, Martín-Lacave I, Calvo JR, Karasek M, et al. Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system. J Clin Endocrinol Metab. 2005;90(2):992-1000. [DOI:10.1210/jc.2004-1429] [PMID]
13. Florido J, Rodriguez-Santana C, Martinez-Ruiz L, López-Rodríguez A, Acuña-Castroviejo D, Rusanova I, et al. Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells. Antioxidants (Basel). 2022;11(8):1621. [DOI:10.3390/antiox11081621] [PMID] []
14. Fan LL, Sun GP, Wei W, Wang ZG, Ge L, Fu WZ, et al. Melatonin and doxorubicin synergistically induce cell apoptosis in human hepatoma cell lines. World J Gastroenterol. 2010;16(12):1473-81. [DOI:10.3748/wjg.v16.i12.1473] [PMID] []
15. Abdel-Tawab MS, Mostafa Tork O, Mostafa-Hedeab G, Ewaiss Hassan M, Azmy Elberry D. Protective Effects of Quercetin and Melatonin on Indomethacin Induced Gastric Ulcers in Rats. Rep Biochem Mol Biol. 2020;9(3):278-290. [DOI:10.29252/rbmb.9.3.278] [PMID] []
16. Hamzawy M, Elsaid L, Shams A, Rashid L, Mahfouz S, Sharawy N. Study of the effects of cyclooxygenase-2 inhibitor on the promotion of hepatic tumorigenesis in rats fed a high fat diet. J Clin Exp Hepatol. 2015;5(1):14-21. [DOI:10.1016/j.jceh.2014.12.010] [PMID] []
17. Chan YH. Biostatistics102: Quantitative Data - Parametric & Non-parametric Tests. Singapore Med J .2003;44(8): 391-396.
18. Chan YH: Biostatistics 104: Correlational Analysis. Singapore Med J.2003;44(12): 614-619.
19. Ahmed Mobasher M, Galal El-Tantawi H, Samy El-Said K. Metformin Ameliorates Oxidative Stress Induced by Diabetes Mellitus and Hepatocellular Carcinoma in Rats. Rep Biochem Mol Biol. 2020;9(1):115-128. [DOI:10.29252/rbmb.9.1.115] [PMID] []
20. Kurma K, Manches O, Chuffart F, Sturm N, Gharzeddine K, Zhang J, et al. DEN-Induced Rat Model Reproduces Key Features of Human Hepatocellular Carcinoma. Cancers (Basel). 2021;13(19):4981. [DOI:10.3390/cancers13194981] [PMID] []
21. Matter MS, Marquardt JU, Andersen JB, Quintavalle C, Korokhov N, Stauffer JK, et al. Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype. Hepatology. 2016;63:1888-1899. [DOI:10.1002/hep.28487] [PMID] []
22. Xu Y, Guo Q, Wei L. The Emerging Influences of Alpha-Fetoprotein in the Tumorigenesis and Progression of Hepatocellular Carcinoma. Cancers (Basel). 2021;13(20):5096. [DOI:10.3390/cancers13205096] [PMID] []
23. Wang CI, Chu PM, Chen YL, Lin YH, Chen CY. Chemotherapeutic Drug-Regulated Cytokines Might Influence Therapeutic Efficacy in HCC. Int J Mol Sci. 2021;22(24):13627. [DOI:10.3390/ijms222413627] [PMID] []
24. Tarao K, Nozaki A, Ikeda T, Sato A, Komatsu H, Komatsu T, et al. Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment. Cancer Med. 2019;8(3):1054-1065. [DOI:10.1002/cam4.1998] [PMID] []
25. Li W, Jian YB. Antitumor necrosis factor-α antibodies as a novel therapy for hepatocellular carcinoma. Exp Ther Med. 2018;16(2):529-536. [DOI:10.3892/etm.2018.6235] [PMID] []
26. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, et al. REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomized, double-blind, multicenter, phase 3 trial. Lancet Oncol. 2015;16(7):859-70. [DOI:10.1016/S1470-2045(15)00050-9] [PMID]
27. Yang L, Zhang Y, Ma Y, Du J, Gu L, Zheng L, et al. Effect of melatonin on EGF- and VEGF-induced monolayer permeability of HUVECs. Am J Physiol Heart Circ Physiol. 2019;316(5):1178-1191. [DOI:10.1152/ajpheart.00542.2018] [PMID]
28. Taniguchi K, Karin M. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18(5):309-324. [DOI:10.1038/nri.2017.142] [PMID]
29. Luedde T, Schwabe RF. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2011;8(2):108-18. [DOI:10.1038/nrgastro.2010.213] [PMID] []
30. Wen X, Wu Y, Awadasseid A, Tanaka Y, Zhang W. New Advances in Canonical Wnt/β-Catenin Signaling in Cancer. Cancer Manag Res. 2020;12:6987-6998. [DOI:10.2147/CMAR.S258645] [PMID] []
31. Khalaf AM, Fuentes D, Morshid AI, Burke MR, Kaseb AO, Hassan M, et al. Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. J Hepatocell Carcinoma. 2018;5:61-73. [DOI:10.2147/JHC.S156701] [PMID] []
32. Cai WY, Wei TZ, Luo QC, Wu QW, Liu QF, Yang M, et al. The Wnt-β-catenin pathway represses let-7 microRNA expression through transactivation of Lin28 to augment breast cancer stem cell expansion. J Cell Sci. 2013;126(13):2877-89. [DOI:10.1242/jcs.123810] [PMID]
33. Tang H, Ma M, Dai J, Cui C, Si L, Sheng X, et al. miR-let-7b and miR-let-7c suppress tumorigenesis of human mucosal melanoma and enhance the sensitivity to chemotherapy. Journal of Experimental & Clinical Cancer Research. 2019;38:1-14 [DOI:10.1186/s13046-019-1190-3] [PMID] []
34. Hui L, Zheng F, Bo Y, Sen-Lin M, Ai-Jun L, Wei-Ping Z, Yong-Jie Z, Lei Y. MicroRNA let-7b inhibits cell proliferation via upregulation of p21 in hepatocellular carcinoma. Cell Biosci. 2020; 1(10):83. [DOI:10.1186/s13578-020-00443-x] [PMID] []
35. Kurt AS, Strobl K, Ruiz P, Osborn G, Chester T, Dawson L, et al. IL-2 availability regulates the tissue-specific phenotype of murine intra-hepatic Tregs. Front. Immunol. 2022;13:1040031. [DOI:10.3389/fimmu.2022.1040031] [PMID] []
36. Ji K, Lin K, Wang Y, Du L, Xu C, He N, et al. TAZ inhibition promotes IL-2-induced apoptosis of hepatocellular carcinoma cells by activating the JNK/F-actin/mitochondrial fission pathway. Cancer Cell Int. 2018;(18):117 [DOI:10.1186/s12935-018-0615-y] [PMID] []
37. Cutando A, López-Valverde A, Arias-Santiago S, DE Vicente J, DE Diego RG. Role of melatonin in cancer treatment. Anticancer Res. 2012;32(7):2747-53.
38. Mao L, Dauchy RT, Blask DE, Slakey LM, Xiang S, Yuan L, et al. Circadian gating of epithelial-to-mesenchymal transition in breast cancer cells via melatonin-regulation of GSK3β. Mol Endocrinol. 2012;26(11):1808-20. [DOI:10.1210/me.2012-1071] [PMID] []
Send email to the article author
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
