Tsuji Keita, Utsunomiya Hiroki, Miki Yasuhiro, Hanihara Mayu, Fue Misaki, Takagi Kiyoshi, Nishimoto Mitsuo, Suzuki Fumihiko, Yaegashi Nobuo, Suzuki Takashi, Ito Kiyoshi
*Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine; †Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University; and ‡Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Int J Gynecol Cancer. 2017 May;27(4):643-650. doi: 10.1097/IGC.0000000000000995.
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.
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.
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.
Retinoic acid might have multiple antitumor effects, and RARβ may be a potent therapeutic target in RA treatment for endometrial cancers.
多项研究报道视黄酸（RA）可能用于治疗恶性肿瘤。RA的作用由RA受体（RAR）介导，尤其是RARα/RARβ起到肿瘤抑制作用。然而，其在人类子宫内膜癌中的作用鲜为人知。
在本研究中，我们检测了全反式视黄酸（ATRA）对人子宫内膜癌细胞系RL95-2和Hec1A进展的影响。然后我们采用免疫组织化学方法检测了50例子宫内膜癌组织中RARα和RARβ的表达。
我们发现ATRA对RL95-2细胞的增殖、凋亡和迁移有抑制作用，但对Hec1A细胞无此作用。单独敲低RARα或RARβ不能消除ATRA对RL95-2细胞增殖的抑制作用，但同时敲低RARα和RARβ可阻断其对增殖的影响。敲低RARα和RARβ可剂量依赖性地降低ATRA对迁移的抑制作用，但敲低RARβ的效果比敲低RARα更显著。我们在基因芯片和实时逆转录聚合酶链反应中证实RARβ基因受ATRA直接调控。此外，RARβ激动剂（BMS453）显著抑制RL95-2细胞的增殖。在免疫组织化学分析中，RARα表达与肿瘤分级呈正相关，而RARβ在子宫内膜癌中表现出相反的趋势。
视黄酸可能具有多种抗肿瘤作用，RARβ可能是RA治疗子宫内膜癌的有效治疗靶点。
