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

Abstract

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 for evaluating the function of MT. Cell viability, apoptosis, and migration were detected by CCK-8, flow cytometry, and transwell assays, respectively. The mRNA and protein expression 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, which negatively regulated 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-midiated PIM1.

Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer

“…A similar effect has been observed in LN229 cells, a human-derived glioblastoma cell line. The results obtained by using this model have shown that melatonin has an inhibitory effect on tumor growth and migration by upregulating the expression of miR-16-5p [ 138 ]. MicroRNA-34a is considered another inhibitor of the EMT, and it has been described that its protective effect against breast cancer invasion and metastasis is accomplished by the inhibition of TWIST1 [ 139 ].…”

Role of melatonin in carcinogenesis and metastasis: From mechanistic insights to intermeshed networks of noncoding RNAs

“…MiR-16-5p inhibition results in the impairment of melatonin-mediated antitumor effects on LN-229 cells, while inhibition of PIM1 causes reversal of the effects of miR-16-5p inhibitors in melatonin-treated cells. 40 Derlin family proteins are molecular components of ERAD complex. These proteins are involved in the retro-translocation of misfolded and unfolded proteins.…”

“…MiR-16-5p directly targeted PIM1 in melatonin-treated LN229 cells. 40 Matrix metalloproteinases have attracted attention because of their roles in metastasis. MMP7 (matrix metalloproteinase 7) potently fuels the proliferation and invasion of osteosarcoma cells.…”

“…Melatonin stimulated the expression of tumor suppressor miR‐16‐5p in glioblastoma LN‐229 cells. MiR‐16‐5p directly targeted PIM1 in melatonin‐treated LN229 cells 40 …”

“…Melatonin dose‐dependently enhanced the level of miR‐16‐5p in glioblastoma LN‐229 cells. MiR‐16‐5p inhibition results in the impairment of melatonin‐mediated antitumor effects on LN‐229 cells, while inhibition of PIM1 causes reversal of the effects of miR‐16‐5p inhibitors in melatonin‐treated cells 40 …”