Department of Pathology, Osaka University Graduate School of Medicine, Yamada-Oka 2-2, Suita 565-0871, Japan.
Biochem Biophys Res Commun. 2013 Nov 1;440(4):731-6. doi: 10.1016/j.bbrc.2013.09.139. Epub 2013 Oct 8.
Cancers consist of heterogeneous populations. Recently, it has been demonstrated that cells with tumorigenic potential are limited to a small population, called cancer-initiating cells (CICs). Aldehyde dehydrogenase 1 (ALDH1) is one of the markers of CICs. We previously reported that ALDH1-high cases of uterine endometrioid adenocarcinoma showed poor prognosis, and ALDH1-high population of endometrioid adenocarcinoma cell line was more tumorigenic, resistant to anti-cancer drugs, and invasive than ALDH1-low population. Here, the regulatory signaling for ALDH1 was examined. The inhibition of TGF-β signaling increased ALDH1-high population. Among TGF-β family members, Nodal expression and ALDH1 expression levels were mutually exclusive. Immunohistochemical analysis on clinical samples revealed Nodal-high tumor cells to be ALDH-low and vise versa, suggesting that Nodal may inhibit ALDH1 expression via stimulating TGF-β signaling in uterine endometrioid adenocarcinoma. In fact, the addition of Nodal to endometrioid adenocarcinoma cell line reduced ALDH1-high population. Although ALDH1 mRNA level was not affected, the amount of ALDH1 protein appeared to be reduce by Nodal through ubiquitine-proteasome pathway. The regulation of TGF-β signaling might be a novel therapeutic target of CICs in endometrioid adenocarcinoma.
癌症由异质群体组成。最近，已经证明具有致瘤潜力的细胞仅限于一小部分，称为癌症起始细胞（CICs）。醛脱氢酶 1（ALDH1）是 CICs 的标志物之一。我们之前报道过，子宫子宫内膜样腺癌中 ALDH1 高的病例预后较差，而子宫内膜样腺癌细胞系中 ALDH1 高的群体比 ALDH1 低的群体具有更强的致瘤性、抗药性和侵袭性。在这里，检查了 ALDH1 的调节信号。TGF-β 信号的抑制增加了 ALDH1 高的群体。在 TGF-β 家族成员中，Nodal 的表达和 ALDH1 的表达水平是相互排斥的。对临床样本的免疫组织化学分析表明，Nodal 高的肿瘤细胞是 ALDH1 低的，反之亦然，这表明 Nodal 可能通过刺激 TGF-β 信号通路在子宫子宫内膜样腺癌中抑制 ALDH1 表达。事实上，Nodal 添加到子宫内膜样腺癌细胞系中会减少 ALDH1 高的群体。尽管 ALDH1 mRNA 水平不受影响，但 Nodal 通过泛素-蛋白酶体途径似乎会减少 ALDH1 蛋白的数量。调节 TGF-β 信号可能是子宫内膜样腺癌中 CICs 的一个新的治疗靶点。
