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Retinoids Decrease Soluble MICA Concentration by Inhibiting the Enzymatic Activity of ADAM9 and ADAM10.

Yumi Otoyama1, Jun Arai2, Kaku Goto3

  • 1Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Anticancer Research
|May 6, 2021
PubMed
Summary

Retinoids reduce soluble MICA (sMICA) in hepatocellular carcinoma (HCC) cells by inhibiting ADAM9 and ADAM10. This effect is mediated by retinoid X receptors (RXRs), suggesting retinoids as potential HCC treatments.

Keywords:
ADAM10ADAM9HCC treatmentMICAretinoids

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Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • MHC class I polypeptide-related sequence A (MICA) is associated with hepatocellular carcinoma (HCC) development.
  • Decreasing soluble MICA (sMICA) enhances natural killer (NK) cell-mediated cytotoxicity.
  • ADAM9 expression in HCC correlates with poor prognosis and its suppression reduces sMICA.

Purpose of the Study:

  • To investigate the potential of FDA-approved drugs in modulating sMICA levels in HCC.
  • To explore the role of retinoids and their receptors in regulating MICA shedding in HCC.

Main Methods:

  • Screening of FDA-approved drugs for inhibition of ADAM9 and ADAM10.
  • Treatment of human HCC cell lines (PLC/PRF/5 and HepG2) with retinoids.
  • Measurement of sMICA levels using ELISA.
  • Knockdown of retinoid X receptors (RXRs) and retinoic acid receptors (RARs) using siRNA.

Main Results:

  • Retinoids were identified as potent inhibitors of ADAM9 and ADAM10 in vitro.
  • Retinoid treatment significantly reduced sMICA levels in human HCC cells.
  • The reduction in sMICA by retinoids was dependent on the retinoid receptor RXRα.

Conclusions:

  • Retinoids demonstrate potential as novel therapeutic agents for hepatocellular carcinoma.
  • Targeting MICA shedding via retinoid-induced inhibition of ADAM metalloproteinases offers a new strategy for HCC treatment.