Radioresistance is a major obstacle in hepatocellular carcinoma (HCC) radiotherapy. Aberrant expression of long non-coding RNA (lncRNA) has been postulated to be implicated in the development of HCC radioresistance. We investigated the role of lncRNA nuclear enriched abundant transcript 1_2 (NEAT1_2) in radioresistance of HCC and its molecular mechanism in this study. We found that NEAT1_2 and WEE1 were upregulated, and miR-101-3p was downregulated in HCC tissues, as well as HCC cell lines. Downregulation of WEE1 sensitized the radiosensitivity of HCC cells, as evidenced by decreased survival fractions of Huh7 and PLC5 cells and increased percentage of apoptotic cells. Also, knockdown of NEAT1_2 exerted a reinforcing effect on the radiosensitivity of HCC cells. In addition, WEE1 was confirmed as a direct target of miR-101-3p. Upregulation of miR-101-3p obviously decreased the mRNA and protein levels of WEE1 compared with that in the miR-NC group, while transfection of anta-miR-101-3p presented the opposite effects. In parallel, NEAT1_2 was identified to interact with miR-101-3p, and NEAT1_2 upregulated the expression of WEE1 in Huh7 cells through sponging miR-101-3p. Besides, the reinforcing effect of NEAT1_2 silencing could be attenuated by downregulation of miR-101-3p. To conclude, our results support the concept that downregulation of lncRNA NEAT1_2 radiosensitizes hepatocellular carcinoma cells through regulation of miR-101-3p/WEE1 axis.

O-GlcNAcylation is a monosaccharide modification by a residue of N-acetylglucosamine (GlcNAc) attached to serine or threonine moieties on nuclear and cytoplasmic proteins. O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Increasing evidence suggests that O-GlcNAcylation is involved in a variety of human cancers. However, the exact role of O-GlcNAcylation in tumor progression remains unclear. Here, we show that O-GlcNAcylation accelerates oncogenic phenotypes of gastric cancer. First, cell models with increased or decreased O-GlcNAcylation were constructed by OGT overexpression, downregulation of OGA activity with specific inhibitor Thiamet-G, or silence of OGT. MTT assays indicated that O-GlcNAcylation increased proliferation of gastric cancer cells. Soft agar assay and Transwell assays showed that O-GlcNAcylation significantly enhanced cellular colony formation, migration, and invasion in vitro. Akt1 activity was stimulated by upregulation of phosphorylation at Ser473 mediated by elevated O-GlcNAcylation. The enhanced cell invasion by Thiamet-G treatment was suppressed by PI3K inhibitor LY294002. Although the cell invasion induced by Thiamet-G was reduced by Akt1 shRNA, it was still higher in comparison with that to the control (cells with Akt1 shRNA alone). And Akt1 overexpression promoted Thiamet-G-induced cell invasion. These results suggested that O-GlcNAcylation enhanced oncogenic phenotypes possibly partially involving PI3K/Akt signaling pathway.

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Has_circ_0008583 is reported to be involved in the progression of hepatocellular carcinoma (HCC), while its biological role in HCC remains unclear. Here, the qRT-PCR was used to detect the expression of has_circ_0008583. The CCK-8 kit was performed to measure cell proliferation. The cell migration and invasion were evaluated by Transwell. A dual-luciferase reporter assay was performed to confirm the target combination between the genes in has_circ_0008583/miR-1301-3p/METTL3 axis. The in vivo role of has_circ_0008583 was verified by murine xenograft assay. Our data showed that hsa_circ_0008583 was upregulated in HCC tissues and cells. Hsa_circ_0008583 overexpression promoted Hep3B cell proliferation, migration and invasion, but hsa_circ_0008583 silencing had an opposing influence. MiR-1301-3p is directly bound to hsa_circ_0008583 and METTL3. MiR-1301-3p overexpression or METTL3 knockdown could partially counteract hsa_circ_0008583 overexpression-mediated influence on HCC cell behaviors. In addition, hsa_circ_0008583 depletion inhibits HCC tumor growth in vivo . In conclusion, hsa_circ_0008583 promotes HCC progression through the miR-1301-3p/METTL3 axis.

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