This study aimed to explore the role of lncRNA GAS5 in the regulation of the
killing effect of NK cells on liver cancer. Compared with a control group,
lncRNA GAS5, RUNX3, and NCR1 were down-regulated in NK cells of patients with
liver cancer, whereas miR-544 expression was up-regulated in NK cells of
patients with liver cancer. Activated NK cells had higher IFN-γ level. Knockdown
of GAS5 in activated NK cells decreased IFN-γ secretion, NK cell cytotoxicity,
the percentage of CD107a+ NK cells, and the apoptosis rate of HepG2 and Huh7
cells. We also proved the interaction of GAS5 and miR-544, and the negative
regulation role of GAS5 on miR-544. GAS5 overexpression in activated NK cells
increased RUNX3 expression, IFN-γ secretion, the NK cell cytotoxicity, the
percentage of CD107a+ NK cells, and the apoptosis rate of HepG2 cells, while
miR-544 mimic abolished the promotion effect of GAS5 overexpression. Finally,
in vivo experiments indicated an inhibition effect of GAS5
in tumor growth. LncRNA GAS5 overexpression enhances the killing effect of NK
cell on liver cancer through regulating miR-544/RUNX3.
Glypican-3 (GPC3) is a widely used immunohistochemical marker for hepatocellular carcinoma (HCC); however, its prognostic value is unclear. Immunohistochemical evaluation of GPC3 expression was performed on 300 postoperative HCC tissue samples with paired adjacent non-tumor tissues on tissue microarray sections. The integral optic density, representing the expression level of GPC3 in each HCC sample, was calculated using Image-Pro Plus. The outcome-based cut-point optimization was performed using X-tile software. GPC3 was highly expressed in HCC tissues compared with adjacent non-tumor tissues. The expression level of GPC3 was significantly correlated with overall survival (OS) and time to recurrence (TTR). The lower the level of GPC3 expression in HCC tissue, the poorer the observed prognosis. Univariate and multivariate analyses showed that the expression level of GPC3 in HCC was an independent prognostic factor for both OS and TTR. In conclusion, GPC3 expression is an independent prognostic factor for postoperative HCC, and low expression levels of GPC3 in HCC may indicate poor outcome.
TNF-related apoptosis-inducing ligand (TRAIL), which is a member of the TNF superfamily, can induce tumor cell apoptosis. However, multiple types of tumor, including hepatocellular carcinoma, show tolerance to TRAIL. Previous studies have demonstrated that tumor cells usually change their expression profile of microRNA (miRNA) to obtain the ability of tolerance to drugs. However, whether such change of miRNA on TRAIL sensitivity is seen in hepatocellular carcinoma still needs to be explored. In this study, we observed overexpression of miR-106b in both HCC patients’ tumor tissues and cell lines. Furthermore, we found that overexpression of miR-106b is associated with the sensitivity of TRAIL to HCC. Silencing of miR-106b with antisense oligonucleotide (anti-miR-106b) is proved to enhance the TRAIL-induced apoptosis and reduce the acquired drug resistance to TRAIL in HCC. Mechanically, we didn't observe the obvious change of pro-apoptotic proteins (Bax and Bid) and anti-apoptotic proteins (Bcl-2, Mcl-1 and Bcl-xl) after treatment of anti-miR-106b. However, we used the methods of bioinformatics, flow cytometry, cellular and molecular methods to prove that miR-106b directly targeted to death receptor 4 (DR4) 3′-UTR (3′-Untranslated Regions). MiR-106b inhibitors induced increase of DR4 expression and therefore enhancing TRAIL-mediated apoptosis in HCC. In summary, these results suggest the application of miR-106b inhibitors in HCC treatment. Combination with miR-106b inhibitors and TRAIL may be a novel clinical treatment method on HCC treatment in the future.
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