LncRNA MEG3 contributes to adenosine‐induced cytotoxicity in hepatoma HepG2 cells by downregulated ILF3 and autophagy inhibition via regulation PI3K‐AKT‐mTOR and beclin‐1 signaling pathway

Adenosine is a promising cytotoxic reagent for tumors, long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been indicated to play critical roles in tumorigenesis, ILF3 has been recognized as a MEG3‐binding protein, however, the roles of adenosine and MEG3 on hepatoma are still ambiguo...

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Published in:Journal of cellular biochemistry 2019-10, Vol.120 (10), p.18172-18185
Main Authors: Pu, Zejin, Wu, Lingfei, Guo, Yitian, Li, Guoping, Xiang, Mengqi, Liu, Lixuan, Zhan, Haolian, Zhou, Xiaotao, Tan, Hui
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Adenosine
AKT protein
Apoptosis
Autophagy
beclin‐1
Cell migration
Cell viability
Cytotoxicity
Gene expression
Genetic transformation
Hepatoma
ILF3
Inhibition
Kinases
Liver cancer
MEG3
Phagocytosis
Phagosomes
PI3K‐AKT‐mTOR
Proteins
Reagents
Ribonucleic acid
RNA
Signal transduction
Signaling
siRNA
TOR protein
Toxicity
Tumorigenesis
Tumors
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Summary:Adenosine is a promising cytotoxic reagent for tumors, long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been indicated to play critical roles in tumorigenesis, ILF3 has been recognized as a MEG3‐binding protein, however, the roles of adenosine and MEG3 on hepatoma are still ambiguous. To clarify the effects of MEG3 on the adenosine‐induced cytotoxicity in hepatoma, MEG3 and ILF3 lentivirus were transduced into human hepatoma HepG2 cells to stimulate overexpression of MEG3 (OE MEG3) and overexpression of ILF3 (OE ILF3), furthermore, ILF3 small interfering RNA (siRNA) was also applied to downregulate the expression of ILF3. In this study, autophagy was markedly inhibited by low concentration of adenosine, which present by not only inhibited transformation from LC3‐I to LC3‐II and autophagosomes formation, but also the elevation of mTOR and reduction of beclin‐1 proteins. Furthermore, low concentration of adenosine also exerted marked cytotoxicity representing induced cell apoptosis together with reductions of cell viability and migration, which were also markedly enhanced by OE MEG3. Novelly and excitingly, adenosine markedly stimulated MEG3 expression, OE MEG3 markedly decreased the ILF3 expression in HepG2 cells, and the adenosine‐induced autophagy inhibition, together with the ratio of p‐PI3K/PI3K, p‐AKT/AKT, and p‐mTOR/mTOR were also boosted by OE MEG3. More interestingly, OE ILF3 increased autophagy, whereas downregulated ILF3, especially in the case of adenosine, led to marked autophagy inhibition by decreasing beclin‐1. The present study demonstrates autophagy inhibition is involved in the adenosine‐induced cytotoxicity in HepG2 cells, the cytotoxicity can be synergized by OE MEG3 via downregulated ILF3 to activate PI3K/Akt/mTOR and inactivate the beclin‐1 signaling pathway. In conclusion, MEG3 and inhibition of autophagy might be potential targets for augmenting adenosine‐induced cytotoxicity in hepatoma. Our results reveal low concentration of adenosine induces apoptosis, decreases the cell viability, and inhibits cell migration of human hepatoma HepG2 cells, all of above are correlated with low concentration of adenosine‐induced inhibition of autophagy. LncRNA MEG3 is low expression in hepatoma, and overexpression of MEG3 enhances the antitumor effects of adenosine by inhibition of autophagy, furthermore, downregulated ILF3, the PI3K/AKT/mTOR and beclin‐1 signaling pathway are involved in these process. Hence, low concentration of
ISSN:0730-2312
1097-4644
DOI:10.1002/jcb.29123