Yang Yi, Cheng Bai-Jun, Jian Hong, Chen Zhi-Wei, Zhao Yi, Yu Yong-Feng, Li Zi-Ming, Liao Mei-Lin, Lu Shun
Department of Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University Shanghai 200030, China.
Am J Transl Res. 2017 Feb 15;9(2):700-707. eCollection 2017.
Rapid growth of tumor cells needs to consume large amounts of oxygen and glucose, due to lack of blood supply within the tumor, cells live in an environment that lack of oxygen and nutrients. This environment results in endoplasmic reticulum (ER) stress and activates the UPR (unfolded protein response). More and more evidence suggests UPR provides a growth signal pathway required for tumor growth. In the present study, we investigated the relationship between XBP1, one transcription factor in UPR, and the expression of LOX. We found that ER stress induces high expression of XBP1, one transcription factor in UPR, in both 2D culture and 3D culture; but only promotes growth of lung adenocarcinoma cells in in vitro 3D culture other than 2D culture. In 3D culture, we further showed that knockdown XBP1 expression can block Tm/Tg-induced cell growth. LOX genes may be key downstream effector of XBP1. Knockdown LOX expression can partially block XBP1-induced cell growth. Then we showed XBP1 suppressed by RNA interference (RNAi) can reduce the expression of LOX. For the first time, it is being shown that XBP1 can regulate the expression of LOX to promote cell growth.
肿瘤细胞的快速生长需要消耗大量的氧气和葡萄糖，由于肿瘤内部缺乏血液供应，细胞处于缺氧和营养物质匮乏的环境中。这种环境会导致内质网（ER）应激并激活未折叠蛋白反应（UPR）。越来越多的证据表明，UPR为肿瘤生长提供了一条必要的生长信号通路。在本研究中，我们调查了UPR中的一种转录因子XBP1与赖氨氧化酶（LOX）表达之间的关系。我们发现，内质网应激在二维培养和三维培养中均能诱导UPR中的一种转录因子XBP1的高表达；但仅在体外三维培养而非二维培养中促进肺腺癌细胞的生长。在三维培养中，我们进一步表明，敲低XBP1的表达可阻断衣霉素/噻苯酰胺（Tm/Tg）诱导的细胞生长。LOX基因可能是XBP1关键的下游效应因子。敲低LOX的表达可部分阻断XBP1诱导的细胞生长。然后我们表明，通过RNA干扰（RNAi）抑制XBP1可降低LOX的表达。首次证明XBP1可调节LOX的表达以促进细胞生长。
