MHC class I-related chain A (
MICA) is a
ligand for the NKG2D-activating immunoreceptor that mediates activation of natural killer (NK) cells. The ectodomain of
MICA is shed from
tumor cells, which may be an important means of evading antitumor immunity. We previously reported that patients with
hepatocellular carcinoma (HCC) display high levels of soluble
MICA in circulation, which could be downregulated by
chemotherapy. The present study shows that anti-HCC drugs suppress
MICA ectodomain shedding by inhibiting expression of a
disintegrin and
metalloproteinase 10 (ADAM10). Both ADAM10 and CD44, a typical substrate of the ADAM10
protease, were expressed in human HCC tissues and HCC cells but not in normal liver tissues or cultured hepatocytes.
Small interfering RNA-mediated knockdown experiments revealed that ADAM10 is a critical sheddase for both
MICA and CD44 in HCC cells. Of interest is the finding that
epirubicin clearly downregulated ADAM10 expression and
MICA shedding in HCC cells; its suppressive effect on
MICA shedding was abolished in ADAM10-depleted cells.
Epirubicin treatment also enhanced the NKG2D-mediated NK sensitivity of HCC cells. Patients with HCC had significantly higher levels of serum-soluble CD44, which correlated well with serum-soluble
MICA levels, thus suggesting a close link between ADAM10 activity and
MICA shedding in these patients. Soluble
MICA and CD44 levels were downregulated with a significant correlation in patients treated by transarterial chemoembolization using
epirubicin. In conclusion, anticancer drugs can modulate expression of ADAM10, which is critically involved in
MICA ectodomain shedding.
Epirubicin therapy may have a previously unrecognized effect on antitumor immunity in HCC patients.