Enhancing NK cell cytotoxicity by miR-182 in hepatocellular carcinoma.
OBJECTIVE
NK-cells are the principle defense line against different malignancies. Their activation status is determined by the balance between activating and inhibitory receptors such as NKG2D and NKG2A, respectively. MicroRNAs are crucial post-transcriptional regulators of gene expression, playing key roles in modulating NK-cell development and function. The aim of this study is to investigate the role of miRNAs in regulating the activation and cytotoxic function of NK-cells in HCC.


METHODS
In silico analysis was performed to predict a potential miRNA that might target NKG2D and NKG2A mRNAs. NK-cells were isolated from HCC patients and healthy controls, after which miRNA and mRNA were quantified. Manipulating miRNA expression was performed followed by investigating downstream targets and the cytotoxic activity of NK-cells against Huh-7 cell lines.


RESULTS
NK-cells of HCC patients showed miR-182 overexpression compared to controls. NKG2D and NKG2A were upregulated and downregulated, respectively, in HCC NK-cells. Upon forcing miR-182 expression in the HCC NK-cells, upregulation of both receptors was observed. Finally, miR-182 was reported to induce NK-cell cytotoxicity represented in Perforin-1 upregulation and increase in cytolytic killing of co-cultured Huh-7 cells.


CONCLUSIONS
Our findings suggest that miR-182 may augment NK-cell cytotoxicity against liver cancer via modulating NKG2D and NKG2A expressions.
Department of Pharmacology and Toxicology, German University in Cairo, New Cairo City, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt.
Mohamed M
MM
Abdelrahman
Department of Pharmacology and Toxicology, German University in Cairo, New Cairo City, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt.
Injie O
IO
Fawzy
Department of Pharmacology and Toxicology, German University in Cairo, New Cairo City, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt.
Aya A
AA
Bassiouni
Department of Hepatology, National Liver Institute, Menoufiya University, Menoufiya, Egypt.
Asmaa I
AI
Gomaa
Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt.
Gamal
G
Esmat
Department of Hepatology, National Liver Institute, Menoufiya University, Menoufiya, Egypt.
Imam
I
Waked
Department of Biology, American University in Cairo, New Cairo, Egypt. Electronic address: a.ihab@aucegypt.edu.
Ahmed I
AI
Abdelaziz
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D019295:Computational Biology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology*; D035683:MicroRNAs / Q000235:genetics*; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000235:genetics / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
C527085:KLRK1 protein, human; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K
HCC; MiR-182; MicroRNAs; NKG2A; NKG2D; Natural killer cells