Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, 060-8556, Japan; Department of Urology, School of Medicine, Sapporo Medical University, Sapporo, 060-8556, Japan.
Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, 060-8556, Japan.
Biochem Biophys Res Commun. 2021 May 7;552:128-135. doi: 10.1016/j.bbrc.2021.03.038. Epub 2021 Mar 19.
Previously, we investigated gene expression in a high aldehyde dehydrogenase 1 expression (ALDH1) population of urothelial carcinoma (UC) cells as UC cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) and found that NRG1 expression was upregulated in ALDH1 cells. NRG1 is a trophic factor that contains an epidermal growth factor (EGF)-like domain that signals by stimulating ERBB receptor tyrosine kinases and the cytoplasmic domain. NRG1 has been determined to be involved in frequent gene fusions with other partners in several malignancies and has a role in carcinogenesis through the NRG1 EGF-like domain and its cognitive receptor ERBBs. We thus aimed to elucidate the function of NRG1 in UC CSCs/CICs in this study. Both NRG1α and NRG1-β1 were preferentially expressed in ALDH1 cells compared with ALDH1 cells; however, siRNA experiments revealed that NRG1-β1 but not NRG1-α has a role in sphere formation. The EGF-like domain of NRG1 had a role in sphere formation of UC cells to some extent but was not essential. The intracellular domain of NRG1 did not have a role in sphere-formation. Inhibition of γ-secretase suppressed sphere formation. These findings indicate that cleavage of NRG1-β1 by γ-secretase plays an important role in UC CSC/CIC proliferation; however, the downstream targets of NRG1-β1 remain elusive.
先前，我们研究了高醛脱氢酶 1 表达（ALDH1）的尿路上皮癌（UC）细胞群体中的基因表达，将其作为 UC 类癌干细胞（CSCs）/癌症起始细胞（CICs），并发现 NRG1 在 ALDH1 细胞中上调。NRG1 是一种神经营养因子，含有表皮生长因子（EGF）样结构域，通过刺激 ERBB 受体酪氨酸激酶和细胞质结构域来发挥信号作用。NRG1 已被确定参与多种恶性肿瘤中与其他伙伴的频繁基因融合，并通过 NRG1 EGF 样结构域及其认知受体 ERBBs 在致癌作用中发挥作用。因此，我们旨在阐明 NRG1 在 UC CSCs/CICs 中的功能。与 ALDH1 细胞相比，NRG1α和 NRG1-β1 均优先在 ALDH1 细胞中表达；然而，siRNA 实验表明，NRG1-β1 而不是 NRG1-α 在球体形成中发挥作用。NRG1 的 EGF 样结构域在一定程度上参与了 UC 细胞球体的形成，但不是必需的。NRG1 的细胞内结构域在球体形成中不起作用。γ-分泌酶的抑制作用抑制了球体的形成。这些发现表明，NRG1-β1 被 γ-分泌酶切割在 UC CSC/CIC 增殖中起着重要作用；然而，NRG1-β1 的下游靶标仍不清楚。
