Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
Ewha Research Center for Systems Biology, Ewha Womans University, Seoul, Republic of Korea.
Cell Death Dis. 2021 Apr 15;12(4):407. doi: 10.1038/s41419-021-03675-y.
In this study, we report a novel function of FCN3 (Ficolin 3), a secreted lectin capable of activating the complement pathway, as a tumor suppressor of lung adenocarcinoma (LUAD). First, the expression of FCN3 was strongly down-regulated in cancer tissues compared to matched normal lung tissues, and down-regulation of FCN3 was shown to be significantly correlated with increased mortality among LUAD patients. Interestingly, while ectopic expression of FCN3 led to cell cycle arrest and apoptosis in A549 and H23 cells derived from LUAD, the secreted form of the protein had no effect on the cells. Rather, we found evidence indicating that activation of the unfolded protein response from endoplasmic reticulum (ER) stress is induced by ectopic expression of FCN3. Consistently, inhibition of ER stress response led to enhanced survival of the LUAD cells. Of note, the fibrinogen domain, which is not secreted, turned out to be both necessary and sufficient for induction of apoptosis when localized to ER, consistent with our proposed mechanism. Collectively, our data indicate that FCN3 is a tumor suppressor gene functioning through induction of ER stress.
在这项研究中，我们报告了一种新的 FCN3（ficolin 3）功能，FCN3 是一种能够激活补体途径的分泌型凝集素，作为肺腺癌 (LUAD) 的肿瘤抑制因子。首先，与匹配的正常肺组织相比，FCN3 在癌组织中的表达明显下调，FCN3 的下调与 LUAD 患者死亡率的增加显著相关。有趣的是，虽然外源性表达 FCN3 导致源自 LUAD 的 A549 和 H23 细胞的细胞周期停滞和细胞凋亡，但该蛋白的分泌形式对细胞没有影响。相反，我们发现证据表明，内质网 (ER) 应激中的未折叠蛋白反应的激活是由 FCN3 的异位表达诱导的。一致地，抑制 ER 应激反应导致 LUAD 细胞的存活率增加。值得注意的是，纤维蛋白原结构域，不能分泌，当定位于 ER 时，结果证明对于诱导细胞凋亡是必需和充分的，与我们提出的机制一致。总的来说，我们的数据表明 FCN3 是一种通过诱导 ER 应激发挥作用的肿瘤抑制基因。
