Department of Gastroenterological Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa-ward, Yokohama, Kanagawa, 236-0004, Japan.
Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, 4-57 Urafunecho, Minami-ward, Yokohama, Kanagawa, 232-0024, Japan.
Breast Cancer Res Treat. 2018 Aug;170(3):507-516. doi: 10.1007/s10549-018-4793-z. Epub 2018 Apr 24.
Aldehyde dehydrogenase1 (ALDH1) is widely accepted as a stem cell marker for normal breast as well as in breast cancer. Although the clinical impact of ALDH1 was observed in our previous study, we do not know how ALDH1 affects stem cell features resulting in worsening of prognosis in breast cancer. The purpose of this study is to explore ALDH1-related gene and its function on cancer stem cell (CSC).
In five cases of ALDH1-positive triple-negative breast cancer, mRNA expression profile was compared between ALDH1-positive and ALDH1-negative cells by Affymetrix microarray analysis after microdissection. Among the genes modulated in ALDH1-positive cells, we focused on H19, which encodes a long non-coding RNA, in this study. An in-vitro study was conducted with H19 siRNA in HCC1934 and iCSCL10A cell lines. The association of H19 with prognosis was examined in 180 breast cancer cases.
Network analysis revealed the existence of five genes related with H19, including miR-103, miR-107, let-7, miR-29b-1, and Trx. In-vitro analysis showed that suppression of H19 using siRNA reduces sphere formation capacity in both HCC1934 and iCSCL10A cell lines. In clinical studies, H19 expression was associated with hormone negativity, tumor size, and nodal status. Patients with H19 expression had significantly poor disease-free survival (DFS) (26.3 vs. 64.8% at 5 years, p = 0.001) and overall survival (OS) (28.9 vs. 68.3% at 5 years, p = 0.004). The effect of H19 expression on prognosis was the most significant in triple-negative breast cancer compared to that in other subtypes (20.0 vs. 65.4% at 5 years DFS, p = 0.012, 20.0 vs. 69.2% at 5 years OS, p = 0.016).
This study indicated that H19 was associated with stem cell phenotype in ALDH1-positive breast cancer. H19 regulates CSC and is associated with poor prognosis in breast cancer patients, particularly in triple-negative subtype.
醛脱氢酶 1（ALDH1）被广泛认为是正常乳腺以及乳腺癌的干细胞标志物。尽管我们之前的研究观察到了 ALDH1 的临床影响，但我们不知道 ALDH1 如何影响干细胞特征，从而导致乳腺癌预后恶化。本研究旨在探讨 ALDH1 相关基因及其在癌症干细胞（CSC）中的功能。
在 5 例 ALDH1 阳性三阴性乳腺癌中，通过微切割后 Affymetrix 微阵列分析比较 ALDH1 阳性和 ALDH1 阴性细胞之间的 mRNA 表达谱。在 ALDH1 阳性细胞中调节的基因中，我们在这项研究中重点关注编码长非编码 RNA 的 H19。在 HCC1934 和 iCSCL10A 细胞系中进行了 H19 siRNA 的体外研究。在 180 例乳腺癌病例中检测了 H19 与预后的相关性。
网络分析显示存在与 H19 相关的五个基因，包括 miR-103、miR-107、let-7、miR-29b-1 和 Trx。体外分析表明，使用 siRNA 抑制 H19 可降低 HCC1934 和 iCSCL10A 细胞系中球体形成能力。在临床研究中，H19 表达与激素阴性、肿瘤大小和淋巴结状态相关。H19 表达的患者无病生存（DFS）（5 年时分别为 26.3%和 64.8%，p=0.001）和总生存（OS）（5 年时分别为 28.9%和 68.3%，p=0.004）显著较差。与其他亚型相比，H19 表达对预后的影响在三阴性乳腺癌中最为显著（5 年 DFS 时分别为 20.0%和 65.4%，p=0.012，5 年 OS 时分别为 20.0%和 69.2%，p=0.016）。
本研究表明，H19 与 ALDH1 阳性乳腺癌中的干细胞表型有关。H19 调节 CSC，并与乳腺癌患者的不良预后相关，特别是在三阴性亚型中。
