Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma is a common malignant tumor with high mortality. Its malignant proliferation, invasion, and metastasis are closely related to the cellular immune function of the patients. NKG2D is a key activated and type II membrane protein molecule expressed on the surface of almost all NK cells. The human NKG2D gene is 270 kb long, located at 12p12.3–p13.1, and contains 10 exons and 9 introns. The three-dimensional structure of the NKG2D monomeric protein contains two alpha-helices, two beta-lamellae, and four disulfide bonds, and its’ signal of activation is transmitted mainly by the adaptor protein (DAP). NKG2D ligands, including MICA, MICB, and ULBPs, can be widely expressed in hepatoma cells. After a combination of NKG2D and DAP10 in the form of homologous two polymers, the YxxM motif in the cytoplasm is phosphorylated and then signaling pathways are also gradually activated, such as PI3K, PLCγ2, JNK-cJunN, and others. Activated NK cells can enhance the sensitivity to hepatoma cells and specifically dissolve by releasing a variety of cytokines (TNF-α and IFN-γ), perforin, and high expression of FasL, CD16, and TRAIL. NK cells may specifically bind to the over-expressed MICA, MICB, and ULBPs of hepatocellular carcinoma cells through the surface activating receptor NKG2D, which can help to accurately identify hepatoma, play a critical role in anti-hepatoma via the pathway of cytotoxic effects, and obviously delay the poor progress of hepatocellular carcinoma.

Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression

“…When MICA protein is activated on the tumor cell surface, MICA binds to its ligand, NKG2D, on the surface of NK cells to enhance the killing effect of NK cells on tumors [30,31]. Furthermore, all the other NKG2D ligands, MICB and ULBPs (1 to 6), are also binds to NKG2D to show their antitumor immunity [32].…”

Natural Killer Group 2D Receptor and B1a Cells Crosstalk in Post-Hepatitis C Virus Infection Hepatocellular Carcinoma and Cirrhosis

“…Activated NK cells can specifically dissolve hepatomas by releasing various cytokines and perforin and highly expressing FasL, CD16, and TRAIL. 19 Previous data explain that decreases in NKG2D, specifically in NK cells, including NKG2D + NK cells, play a critical anti-hepatoma role.…”

“…This disagreed with the findings of Wang et al, who reported that NKG2D + NK cells play a critical anti-hepatoma role. 19 Another study has found that NKG2D + NK cells are greatly abundant in intrahepatic compartments in patients with HCC and are linked to tumor damage. 21 Regarding B1a cells, Shen et al have reported that tumor-infiltrating IgM + B cells were linked to a better prognosis in solid tumors.…”

“…by releasing various cytokines and perforin and highly expressing FasL, CD16, and TRAIL. 19 Previous data explain that decreases in NKG2D, specifically in NK cells, including NKG2D + NK cells, play a critical anti-hepatoma role. MHC class I polypeptide-related sequence A (MICA) was identified by Goto and Kato (2015) as a susceptibility gene for post-HCV HCC.…”

NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

“…The activating receptor NKG2D is overexpressed in patients with hepatocellular carcinoma (HCC) [97]. NKG2D binding with its ligands on the cell surface may start several signaling pathways such as phosphatidylinositol 3-hydroxy kinase (PI3K), phospholipase C Gamma 2 (PLCG2), c-Jun-NH(2)-terminal kinase (JNK) [98]. This results in increased antitumor properties of the NK cells due to enhancing Antibody-Dependent Cellular Cytotoxicity (ADCC) effects, secreting cytokines and initiating apoptosis.…”