Immune checkpoint blockade (ICB) increasingly being applied as a treatment for advanced HCC.
Hepatocellular carcinoma (HCC) is a malignant disease with high mortality worldwide. In conclusion, this research identifies a novel mechanism by which NNT-AS1 impairs CD4 T cell infiltration via activation of the TGF- β signaling pathway in HCC. In HCC tissues, IHC detection showed that relatively high NNT-AS1 levels were associated with a reduction in infiltrated CD4 lymphocyte numbers. Further mechanistic investigation indicated that NNT-AS1 inhibition significantly decreased the levels of TGF- β, TGFBR1, and SMAD5 in HCC cells. Importantly, the overall survival time of HCC patients who exhibited higher levels of NNT-AS1 expression was significantly shorter than that of HCC patients who had lower levels of NNT-AS1 expression ( P = 0.0402). In addition, the elevated NNT-AS1 levels in cancer tissue were further confirmed by RT-qPCR analysis of HCC cancer tissues ( n = 64) and normal tissues ( n = 26) ( P = 0.0003). In these analyses, RNAscope detection demonstrated that NNT-AS1 levels were significantly increased in HCC cancer tissues ( P = 0.0001). HCC cell lines (HepG2 and Huh7) were used to explore the effects of NNT-AS1 on TGF- β signaling activation. The levels of proteins involved in TGF- β signaling and those of CD4 T lymphocytes were quantified by immunohistochemistry (IHC). High levels of NNT-AS1 were detected in HCC tissues by both RNAscope and real-time quantitative PCR (RT-qPCR) assays. We thus planned to explore the mechanism by which NNT-AS1 activates the TGF- β signaling pathway and inhibits TILs in HCC. The activation of TGF- β signaling inhibits tumor-infiltrating lymphocytes (TILs) and results in tumor immune evasion. However, the molecular mechanism involving NNT-AS1 in HCC remains to be extensively investigated. Nicotinamide nucleotide transhydrogenase-antisense RNA1 (NNT-AS1) is a long noncoding RNA (lncRNA) that has been shown to be overexpressed in hepatocellular carcinoma (HCC).
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