HBx Promotes Liver Cancer Cells to Escape NK‐92 Cell Attack by Mediating ADAM10 to Enzyme Cut MICA/B Shedding From Cancer Cell Membrane

TL;DR

This study shows how HBx helps liver cancer cells avoid immune attacks by cutting MICA/B proteins from their surface using ADAM10.

Contribution

The study reveals a novel mechanism where HBx activates ADAM10 via HIF-1α to shed MICA/B, enabling HCC cells to evade NK-92 cell immunity.

Findings

HBx, MICA/B, and HIF-1α are highly expressed in HBV-infected HCC tissues.

HBx promotes MICA/B shedding by upregulating ADAM10 activity.

Inhibiting ADAM10 or HIF-1α restores MICA/B on HCC cell surfaces and enhances NK-92 cell killing.

Abstract

MICA/B shedding from the membrane of cancer cells can inhibit natural killer (NK) cells from attacking hepatocellular carcinoma (HCC). This study explored the role of HBx in mediating MICA/B shedding. The expression of HBx, MICA/B and HIF‐1α in HBV‐infected HCC was analysed using bioinformatics, and the localization of these proteins in tissues was verified using immunohistochemistry and immunofluorescence. HBx‐related signalling pathways were screened using RNA sequencing and KEGG pathway enrichment analyses. The expression of ADAM10 and MICA/B was detected by Western blotting, and the dynamic changes of MICA/B in the membrane and supernatant were evaluated by flow cytometry and ELISA. The HIF‐1α inhibitor (LW‐6) and ADAM10 inhibitor (GI254023X) were used to treat the HCC cells. The killing effect of NK‐92 cells on HCC cells was evaluated using lactate dehydrogenase release, cytotoxicity assays, clone formation and live‐cell imaging, and the secretion levels of IFN‐γ, IL‐2 and IL‐10 were measured. These results indicated that HBx, MICA/B and HIF‐1α were highly expressed in HBV‐infected HCC tissues. HBx promotes shedding of MICA/B from HCC cell membranes by upregulating the activity of ADAM10. LW‐6 reversed the induction effect of HBx on ADAM10 and GI254023X significantly restored MICA/B levels on the membrane surface of HCC cells. Overexpression of HBx increases the resistance of HCC cells to NK‐92 cells and inhibits the secretion of IFN‐γ, IL‐2 and IL‐10. In conclusion, HBx regulates the expression of ADAM10 by activating the HIF‐1α signalling pathway. ADAM10 cuts MICA/B shedding from the membrane surface of HCC cells, resulting in escape attack by NK‐92 cells.

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