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Basic Science
Retinoic Acid Receptor β: A Potential Therapeutic Target in Retinoic Acid Treatment of Endometrial Cancer
  1. Keita Tsuji, MD, PhD*,
  2. Hiroki Utsunomiya, MD, PhD*,
  3. Yasuhiro Miki, DVM, PhD†,
  4. Mayu Hanihara, MSc*,
  5. Misaki Fue, MSc†,
  6. Kiyoshi Takagi, PhD‡,
  7. Mitsuo Nishimoto, MD, PhD*,
  8. Fumihiko Suzuki, PhD*,
  9. Nobuo Yaegashi, MD, PhD*,
  10. Takashi Suzuki, MD, PhD‡ and
  11. Kiyoshi Ito, MD, PhD†
  1. * Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine;
  2. † Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University; and
  3. ‡ Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan.
  1. Address correspondence and reprint requests to: Yasuhiro Miki, DVM, PhD, Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University, Sendai, 980-8575, Japan. E-mail: miki{at}patholo2.med.tohoku.ac.jp.

Abstract

Objective Several studies have reported that retinoic acid (RA) might be used to treat malignancies. The effects of RA are mediated by the RA receptor (RAR), and RARα/RARβ especially acts as a tumor suppressor. However, little is known about its role in human endometrial cancer.

Materials and Methods In this study, we examined the effects of all-trans RA (ATRA) on progression of human endometrial cancer cell line, RL95-2 and Hec1A. We then examined the expression of RARα and RARβ in 50 endometrial cancer tissues by using immunohistochemistry.

Results We found inhibitory effects of ATRA on cell proliferation, apoptosis, and migration in RL95-2 cells, but not in Hec1A cells. RARα or RARβ knockdown individually could not cancel out the inhibition of cell proliferation by ATRA in RL95-2 cells, but simultaneous knockdown of RARα and RARβ could block its effect on proliferation. RARα and RARβ knockdown dose dependently reduced the inhibition of migration by ATRA, but the effect was more pronounced with RARβ knockdown than with RARα knockdown. We confirmed that RARβ gene was directly regulated by ATRA in microarray and real-time reverse transcription polymerase chain reaction. Furthermore, the RARβ agonist (BMS453) significantly suppressed proliferation of RL95-2 cells. In immunohistochemical analysis, RARα expression was positively correlated with tumor grade, and RARβ showed the opposite tendency in endometrial cancer.

Conclusions Retinoic acid might have multiple antitumor effects, and RARβ may be a potent therapeutic target in RA treatment for endometrial cancers.

  • Retinoic acid receptor α
  • Retinoic acid receptor β
  • All trans retinoic acid
  • Endometrial cancer

https://doi.org/10.1097/IGC.0000000000000995

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    Footnotes

    • The authors declare no conflicts of interest.