Gao Zhihui, Ni Xiaojian, Zheng Bohao, Sun Wentao, Wan Wenze, Liu Han, Ni Xiaoling, Suo Tao, Li Na, Liu Houbao, Shen Sheng
Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China.
Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China.
J Cancer. 2022 Apr 4;13(7):2159-2170. doi: 10.7150/jca.70323. eCollection 2022.
Cholangiocarcinoma (CCA) is one of the most lethal types of solid tumors worldwide. Lymph node metastasis is common in the early stage, which is associated with recurrence and reduced survival time after CCA resection. The molecular pathogenesis of CCA is complex and requires extensive investigation. It involves multiple genomic alterations and the dysregulation of signaling pathways. Biliverdin reductase B (BLVRB) is a non-redundant NAD(P)H-dependent biliverdin reductase that regulates cellular redox status by reducing biliverdin to bilirubin. This study aimed at describing the biological functions and molecular mechanisms of BLVRB in human CCA. Prognostic clinical data showed that low expression BLVRB was associated with poor prognosis and lymph node metastasis. depletion accelerated epithelial-mesenchymal transition (EMT), cell migration and invasion. In contrast, BLVRB overexpression was associated with reduced EMT and cell migration and invasion in CCA. suppression activated Notch signaling, and activated c-Notch enhanced EMT by upregulating Snail expression levels, thereby increasing cell migration and invasion in CCA. Our results identified an unexpected function of BLVRB in CCA migration and invasion through the regulation of Notch/Snail signaling.
胆管癌（CCA）是全球最致命的实体瘤类型之一。淋巴结转移在早期很常见，这与CCA切除术后的复发和生存时间缩短有关。CCA的分子发病机制复杂，需要广泛研究。它涉及多种基因组改变和信号通路的失调。胆绿素还原酶B（BLVRB）是一种非冗余的依赖NAD(P)H的胆绿素还原酶，通过将胆绿素还原为胆红素来调节细胞氧化还原状态。本研究旨在描述BLVRB在人CCA中的生物学功能和分子机制。预后临床数据显示，BLVRB低表达与预后不良和淋巴结转移有关。BLVRB缺失加速上皮-间质转化（EMT）、细胞迁移和侵袭。相反，BLVRB过表达与CCA中EMT、细胞迁移和侵袭减少有关。BLVRB抑制激活Notch信号，激活的c-Notch通过上调Snail表达水平增强EMT，从而增加CCA中的细胞迁移和侵袭。我们的结果通过Notch/Snail信号的调节确定了BLVRB在CCA迁移和侵袭中的意外功能。
