Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 17, Pages -Publisher
MDPI
DOI: 10.3390/ijms22179285
Keywords
natural killer (NK) cell; hepatocellular carcinoma (HCC); NLRP3; MICA; B; xenograft model
Funding
- Priority Research Center Program through the NRF - Korean Ministry of Education, Science, and Technology [2016R1A6A1A03007648]
- National Research Foundation of Korea - Korean Government (MSIT) [2020R1A5A2017323]
- Basic Science Research Program of the National Research Foundation of Korea (NRF) [NRF- 2020R1I1A1A01074412]
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This study demonstrated that HCC patients have reduced NK cell frequency and impaired NK cell function, while NLRP3 expression in HCC cells affects NK cell cancer surveillance. Through the interaction of NKG2D-MICA, NLRP3 KO in HCC cells enhances NK cell immunosurveillance.
Human hepatocellular carcinoma (HCC) is the most common and even worse at prognosis. The patients with HCC which accompanied by other diseases, such as cirrhosis, can be limited in various treatments, such as chemotherapy, not HCC patients without other diseases. NLRP3 inflammasome plays an important role in the innate immune response, but emerging evidence has indicated that the NLRP3 inflammasome is implicated in all stages of cancer development. Various cells express NLRP3 protein through the autocrine or paracrine signaling in their environment, but NK cells do not. The expanding evidence shows that patients who suffer from liver cancers have a low frequency of natural killer (NK) cells, and the function of these cells is also impaired. Thus, we examined how the expression of NLRP3 in HCC cells affects cancer surveillance by NK cells in a state of a co-culture of both cells. When the expression of NLRP3 in HCC cells was ablated, MICA/B on the surface of HCC cells was upregulated through the lowered expression of matrix metalloproteinase. The expression of MICA on the surface of HCC cells interacted with the NKG2D receptor on NK-92 cells, which led to NK cytotoxicity. Furthermore, in a xenograft mice model, NLRP3 KO HCC cells delayed tumor development and metastasis as well as increased the sensitivity to NK cell cytotoxicity. Taken together, NLRP3 KO in HCC could enhance NK immunosurveillance through an interaction of NKG2D-MICA.
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