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Current Neurovascular Research


ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

Melatonin Inhibits the Malignant Progression of Glioblastoma via Regulating miR-16-5p/PIM1

Author(s): Zhaoxian Yan, Xin Zhang, Lin Hua and Lifa Huang*

Volume 19, Issue 1, 2022

Published on: 02 June, 2022

Page: [92 - 99] Pages: 8

DOI: 10.2174/1567202619666220406084947

Price: $65


Objectives: Melatonin (MT) is a pineal hormone with antineoplastic potential. This study aims to explore the therapeutic potential and mechanism of MT on glioblastoma (GBM).

Methods: A human GBM cell line, LN229, was used to evaluate the function of MT. Cell viability, apoptosis, and migration were detected by CCK-8, flow cytometry, and transwell assays, respectively. The mRNA and protein expressions of specific genes were measured by qRT-PCR and western blot, respectively. The regulatory relationship between miR-16-5p and PIM1 was validated by dual luciferase reporter gene assay. A mouse xenograft model was established to prove the anti-tumor effect and related mechanisms of MT in vivo.

Results: MT inhibited the viability and migration and promoted the apoptosis of LN229 cells in a dose-dependent manner. MiR-16-5p was dose-dependently up-regulated by MT in LN229 cells, negatively regulating its target PIM1. MiR-16-5p inhibitor eliminated the anti-tumor effect of MT in LN229 cells, while si-PIM1 reversed the effect of miR-16-5p inhibitor in MT-treated cells. MT inhibited the tumor growth in vivo and MT-induced PIM1 down-regulation was reversed by miR- 16-5p inhibition in tumor tissues.

Conclusions: MT inhibits the malignant progression of GBM via regulating miR-16-5p-mediated PIM1.

Keywords: Glioblastoma, melatonin, microRNA-16-5p, PIM1, malignant progression, in vivo experiments.

« Previous
Le Rhun E, Preusser M, Roth P, et al. Molecular targeted therapy of glioblastoma. Cancer Treat Rev 2019; 80: 101896.
[] [PMID: 31541850]
Eder K, Kalman B. Molecular heterogeneity of glioblastoma and its clinical relevance. Pathol Oncol Res 2014; 20(4): 777-87.
[] [PMID: 25156108]
Batash R, Asna N, Schaffer P, Francis N, Schaffer M. Glioblastoma multiforme, diagnosis and treatment; recent literature review. Curr Med Chem 2017; 24(27): 3002-9.
[] [PMID: 28521700]
Wen PY, Reardon DA. Neuro-oncology in 2015: Progress in glioma diagnosis, classification and treatment. Nat Rev Neurol 2016; 12(2): 69-70.
[] [PMID: 26782337]
Braun K, Ahluwalia MS. Treatment of glioblastoma in older adults. Curr Oncol Rep 2017; 19(12): 81.
[] [PMID: 29075865]
Delgado-López PD, Corrales-García EM. Survival in glioblastoma: A review on the impact of treatment modalities. Clin Transl Oncol 2016; 18(11): 1062-71.
[] [PMID: 26960561]
Long R, Zhu Y, Zhou S. Therapeutic role of melatonin in migraine prophylaxis: A systematic review. Medicine (Baltimore) 2019; 98(3): e14099.
[] [PMID: 30653130]
Claustrat B, Leston J. Melatonin: Physiological effects in humans. Neurochirurgie 2015; 61(2-3): 77-84.
[] [PMID: 25908646]
Tordjman S, Chokron S, Delorme R, et al. Melatonin: pharmacology, functions and therapeutic benefits. Curr Neuropharmacol 2017; 15(3): 434-43.
[] [PMID: 28503116]
Talib WH. Melatonin and cancer hallmarks. Molecules 2018; 23(3): E518.
[] [PMID: 29495398]
Moretti E, Favero G, Rodella LF, Rezzani R. Melatonin’s antineoplastic potential against glioblastoma. Cells 2020; 9(3): E599.
[] [PMID: 32138190]
Zhang Y, Liu Q, Wang F, et al. Melatonin antagonizes hypoxia-mediated glioblastoma cell migration and invasion via inhibition of HIF-1α.. J Pineal Res 2013; 55(2): 121-30.
[] [PMID: 23551342]
Zheng X, Pang B, Gu G, et al. Melatonin inhibits glioblastoma stem-like cells through suppression of ezh2-notch1 signaling axis. Int J Biol Sci 2017; 13(2): 245-53.
[] [PMID: 28255276]
Doğanlar O, Doğanlar ZB, Delen E, Doğan A. The role of melatonin in angio-miR-associated inhibition of tumorigenesis and invasion in human glioblastoma tumour spheroids. Tissue Cell 2021; 73: 101617.
[] [PMID: 34418770]
Wu W, Yu A, Chen K, et al. The oncogene PIM1 contributes to cellular senescence by phosphorylating staphylococcal nuclease domain-containing protein 1 (SND1). Med Sci Monit 2019; 25: 8651-9.
[] [PMID: 31860636]
Cuypers HT, Selten G, Quint W, et al. Murine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region. Cell 1984; 37(1): 141-50.
[] [PMID: 6327049]
Brasó-Maristany F, Filosto S, Catchpole S, et al. PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. Nat Med 2016; 22(11): 1303-13.
[] [PMID: 27775704]
Kim S, Kim W, Kim DH, et al. Resveratrol suppresses gastric cancer cell proliferation and survival through inhibition of PIM-1 kinase activity. Arch Biochem Biophys 2020; 689: 108413.
[] [PMID: 32473133]
Ye C, Zhang C, Huang H, et al. The natural compound myricetin effectively represses the malignant progression of prostate cancer by inhibiting PIM1 and disrupting the PIM1/CXCR4 interaction. Cell Physiol Biochem 2018; 48(3): 1230-44.
[] [PMID: 30045021]
Wang Q, Jiang Y, Guo R, et al. Physcion 8-O-β-glucopyranoside suppresses tumor growth of Hepatocellular carcinoma by downregulating PIM1. Biomed Pharmacother 2017; 92: 451-8.
[] [PMID: 28570979]
Lai SW, Liu YS, Lu DY, Tsai CF. Melatonin modulates the microenvironment of glioblastoma multiforme by targeting sirtuin 1. Nutrients 2019; 11(6): E1343.
[] [PMID: 31207928]
Herzog S, Fink MA, Weitmann K, et al. Pim1 kinase is upregulated in glioblastoma multiforme and mediates tumor cell survival. Neuro-oncol 2015; 17(2): 223-42.
[] [PMID: 25155357]
Ji G, Zhou W, Li X, Du J, Li X, Hao H. Melatonin inhibits proliferation and viability and promotes apoptosis in colorectal cancer cells via upregulation of the microRNA-34a/449a cluster. Mol Med Rep 2021; 23(3): 187.
[] [PMID: 33398374]
Wu J, Tan Z, Li H, et al. Melatonin reduces proliferation and promotes apoptosis of bladder cancer cells by suppressing O-GlcNAcylation of cyclin-dependent-like kinase 5. J Pineal Res 2021; 71(3): e12765.
[] [PMID: 34487576]
Song J, Ma SJ, Luo JH, et al. Melatonin induces the apoptosis and inhibits the proliferation of human gastric cancer cells via blockade of the AKT/MDM2 pathway. Oncol Rep 2018; 39(4): 1975-83.
[] [PMID: 29484412]
Tian QX, Zhang ZH, Ye QL, et al. Melatonin inhibits migration and invasion in lps-stimulated and -unstimulated prostate cancer cells through blocking multiple emt-relative pathways. J Inflamm Res 2021; 14: 2253-65.
[] [PMID: 34079331]
Chen K, Zhu P, Chen W, Luo K, Shi XJ, Zhai W. Melatonin inhibits proliferation, migration, and invasion by inducing ROS-mediated apoptosis via suppression of the PI3K/Akt/mTOR signaling pathway in gallbladder cancer cells. Aging (Albany NY) 2021; 13(18): 22502-15.
[] [PMID: 34580235]
Wang L, Su Y, Choi WS. Melatonin suppresses oral squamous cell carcinomas migration and invasion through blocking fgf19/fgfr 4 sig-naling pathway. Int J Mol Sci 2021; 22(18): 9907.
[] [PMID: 34576070]
Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol 2009; 4(1): 199-227.
[] [PMID: 18817506]
Rezaei O, Honarmand K, Nateghinia S, Taheri M, Ghafouri-Fard S. miRNA signature in glioblastoma: Potential biomarkers and therapeutic targets. Exp Mol Pathol 2020; 117: 104550.
[] [PMID: 33010295]
Zhu C, Huang Q, Zhu H. Melatonin inhibits the proliferation of gastric cancer cells through regulating the mir-16-5p-smad3 pathway. DNA Cell Biol 2018; 37(3): 244-52.
[] [PMID: 29359963]
Ruan L, Qian X. MiR-16-5p inhibits breast cancer by reducing AKT3 to restrain NF-κB pathway. Biosci Rep 2019; 39(8): BSR20191611.
[] [PMID: 31383783]
Gu Z, Li Z, Xu R, et al. miR-16-5p suppresses progression and invasion of osteosarcoma via targeting at Smad3. Front Pharmacol 2020; 11: 1324.
[] [PMID: 32982740]
Cheng B, Ding F, Huang CY, Xiao H, Fei FY, Li J. Role of miR-16-5p in the proliferation and metastasis of hepatocellular carcinoma. Eur Rev Med Pharmacol Sci 2019; 23(1): 137-45.
[PMID: 30657555]
Munson PB, Hall EM, Farina NH, Pass HI, Shukla A. Exosomal miR-16-5p as a target for malignant mesothelioma. Sci Rep 2019; 9(1): 11688.
[] [PMID: 31406207]
Wang F, Wang W, Lu L, et al. MicroRNA 16 5p regulates cell survival, cell cycle and apoptosis by targeting AKT3 in prostate cancer cells. Oncol Rep 2020; 44(3): 1282-92.
[] [PMID: 32705237]
Zhang J, Song Y, Zhang C, et al. Circulating MiR-16-5p and MiR-19b-3p as two novel potential biomarkers to indicate progression of gastric cancer. Theranostics 2015; 5(7): 733-45.
[] [PMID: 25897338]
Moloudizargari M, Moradkhani F, Hekmatirad S, Fallah M, Asghari MH, Reiter RJ. Therapeutic targets of cancer drugs: Modulation by melatonin. Life Sci 2021; 267: 118934.
[] [PMID: 33385405]
Jin D, Lee H. Prioritizing cancer-related microRNAs by integrating microRNA and mRNA datasets. Sci Rep 2016; 6(1): 35350.
[] [PMID: 27734929]
Li JQ, Yang X, Zhou XM. PIM1 gene silencing inhibits proliferation and promotes apoptosis of human esophageal cancer cell line Eca-109. Cancer Biomark 2017; 18(2): 149-54.
[] [PMID: 27983525]
Xue C, He Y, Hu Q, et al. Downregulation of PIM1 regulates glycolysis and suppresses tumor progression in gallbladder cancer. Cancer Manag Res 2018; 10: 5101-12.
[] [PMID: 30464610]

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