The microRNA-99 family modulates hepatitis B virus replication by promoting IGF-1R/PI3K/Akt/mTOR/ULK1 signaling-induced autophagy

Abstract

MicroRNAs are small highly conserved noncoding RNAs that are widely expressed in multicellular organisms and participate in the regulation of various cellular processes including autophagy and viral replication. Evidently, microRNAs are able to modulate host gene expression and thereby inhibit or enhance hepatitis B virus (HBV) replication. The miR-99 family members are highly expressed in the liver. Interestingly, the plasma levels of miR-99 family in the peripheral blood correspond with HBV DNA loads. Thus, we asked whether the miR-99 family regulated HBV replication and analyzed the underlying molecular mechanism. Compared with primary hepatocytes, miR-99 family expression was downregulated in hepatoma cells. Transfection of miR-99a, miR-99b, and miR-100 markedly increased HBV replication, progeny secretion, and antigen expression in hepatoma cells. However, miR-99 family had no effect on HBV transcription and HBV promoter activities, suggesting that they regulate HBV replication at posttranscriptional steps. Consistent with bioinformatic analysis and recent reports, ectopic expression of miR-99 family attenuated IGF-1R/Akt/mTOR pathway signaling and repressed insulin-stimulated activation in hepatoma cells. Moreover, the experimental data demonstrated that the miR-99 family promoted autophagy through mTOR/ULK1 signaling and thereby enhanced HBV replication. In conclusion, the miR-99 family promotes HBV replication posttranscriptionally through IGF-1R/PI3K/Akt/mTOR/ULK1 signaling-induced autophagy.

AMPK and Akt/mTOR signalling pathways participate in glucose‐mediated regulation of hepatitis B virus replication and cellular autophagy

“…Previous studies in HBV transgenic mice have illustrated, for example, that fasting decreases glucose levels but increases HBeAg synthesis in serum. However, autophagy significantly promotes HBsAg and virion production but not HBeAg production, as shown in several early studies (Lin et al, 2017;Lin, Wu, Wang, Kemper, et al, 2019;Lin, Wu, Wang, Liu, et al, 2019). In this study, the expression of transcription factors, including PGC1α, CREB, and ChREBP, was found to be altered by these indicated glucose concentrations in the cell cultures and correlated with changes in the HBV RNAs levels.…”

“…Maintaining energy homeostasis is very important in mammalian physiology. Previously, we tested several mTOR-related pathways and found that SREBP1 was also partly activated to regulate HBV replication (Lin et al, 2017). Herein, HBV replication decreased after 2-DG treatment in HepG2.2.15 cells.…”

“…HBV RNA levels in cells were measured by real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays (Qiagen, 204154) using the primers 5′-CCGTCTGTGCCTTCTCATCT-3′ (forward) and 5′-TAATCTCCTCCCCCAACTCC-3′ (reverse). HBV replicative intermediates (RIs) from intracellular core particles were extracted and detected by Southern blotting as described previously (Lin et al, 2017;J. These primers cover all four HBV RNAs as described previously (Zhang et al, 2011).…”

“…In recent years, many studies demonstrated that HBV replication depended on cellular autophagy, and the AMPK-Akt/mTOR-ULK1-induced autophagy pathway significantly regulates HBV replication (Lin et al, 2017;Lin et al, 2019;J. In recent years, many studies demonstrated that HBV replication depended on cellular autophagy, and the AMPK-Akt/mTOR-ULK1-induced autophagy pathway significantly regulates HBV replication (Lin et al, 2017;Lin et al, 2019;J.…”

Anticancer effect of HOTTIP regulates human pancreatic cancer via the metabotropic glutamate receptor 1 pathway

“…The PI3K/Akt signaling pathway regulates the crucial cellular biological process involved in the genesis and development of cancer, including transcription, translation, metabolism, angiogenesis, apoptosis, proliferation, and regulation of cell cycle progression, migration and invasion of cells (26,27). p-Akt is able to phosphorylate the downstream tyrosine and tryptophan residues, so as to activate downstream factors, cause the apoptosis of suppressor cells, promote cellular proliferation, growth, movement and invasion, and promote tumor angiogenesis (28). In vivo and in vitro experiments have indicated that following restrained activity of the PI3K-Akt signaling pathway, pancreatic cancer cells undergo hindered proliferation, promoted apoptosis and reduced invasive ability (29).…”