Nature killer (NK) cells play a critical role in host innate and adaptive immune defense against viral infections and tumors. NK cells are enriched in liver hematopoietic cells with unique NK repertories and functions to safeguard liver cells against hepatitis virus infection or malignancy transformation. However, accumulating evidences were found that the NK cells were modulated by liver diseases and liver cancers including hepatocellular carcinoma (HCC) and showed impaired functions failing to activate the elimination of the viral-infected cells or tumor cells and were further involved in the pathogenesis of liver injury and inflammation. The full characterization of circulation and intrahepatic NK cell phenotype and function in liver disease and liver cancer has not only provided new insight into the disease pathogenesis but has also discovered new targets for developing new NK cell-based therapeutic strategies. This review will discuss and summarize the NK cell phenotypic and functional changes in liver disease and HCC, and the NK cell-based immunotherapy approaches and progresses for cancers including HCC will also be reviewed.

Lung cancer, which is a leading cause of cancer-related deaths, is diagnosed at a male to female ratio of 2.1:1. Serine-threonine kinase 31 (STK31) is a novel cancer/testis (CT)-related gene that is highly expressed in several types of cancers, such as lung and colorectal cancer, and plays crucial roles in cancer. In the present study, increased expression of STK31 and β-catenin was observed in lung cancer tissues and cell lines. Downregulation of STK31 expression in lung cancer cells significantly inhibited their proliferation by arresting the cell cycle in the G1 phase concurrent with decreased β-catenin, c-myc and cyclin D1 protein levels, while upregulation of STK31 had the opposite effects. In addition, STK31-induced lung cancer cell viability, proliferation, cell cycle progression, and expression of related genes were completely attenuated by a Wnt/β-catenin inhibitor (XAV939). Similar to XAV939, a c-myc inhibitor (10058-F4) also significantly attenuated STK31-induced proliferation and cell cycle progression in lung cancer cells. Inhibiting c-myc and TRRAP significantly decreased the expression of STK31, and a chromatin immunoprecipitation (ChIP) assay confirmed that c-myc directly bound to the STK31 promoter. These results indicated that STK31 may act as an oncogene in lung cancer and that c-myc may be the transcription factor that promotes STK31 expression. Moreover, the results suggested that c-myc can also regulate STK31 expression in a positive feedback loop, and the downregulation of STK31 in lung cancer cells had an inhibitory effect on cell viability, cell proliferation and cell cycle progression, likely by inactivating the Wnt/β-catenin pathway and positive feedback regulation by c-myc.