Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Lab Invest. 2023 Jul;103(7):100130. doi: 10.1016/j.labinv.2023.100130. Epub 2023 Mar 15.
Collectin subfamily member 10 (COLEC10), a C-type lectin mainly expressed in the liver, is involved in the development of hepatocellular carcinoma (HCC). However, its underlying molecular mechanism in HCC progression remains unknown. In this study, reduced COLEC10 expression in tumor tissues was validated using various HCC cohorts and was associated with poor patient prognosis. COLEC10 overexpression attenuated HCC cell growth and migration abilities in vitro and in vivo. We identified that COLEC10 was a novel interactor of 78-kDa glucose-regulated protein (GRP78), a master modulator of the unfolded protein response in the endoplasmic reticulum (ER). COLEC10 overexpression potentiated ER stress in HCC cells, as demonstrated by elevated expression levels of phosphorylated protein kinase RNA-like ER kinase, phosphorylated inositol-requiring protein 1α, activating transcription factor 4, DNA damage-inducible transcript 3, and X-box-binding protein 1s. The ER in COLEC10-overexpressing cells also showed a dilated and fragmented pattern. Mechanistically, COLEC10 overexpression increases GRP78 occupancy through direct binding by the C-terminal carbohydrate recognition domain in the ER, which released and activated the ER stress transducers protein kinase RNA-like ER kinase and phosphorylated inositol-requiring protein 1α, triggering the unfolded protein response activity. COLEC10-overexpressing HCC cells generated a relatively high reactive oxygen species level and switched to apoptotic cell death under sorafenib-treated conditions. Our study provides the first novel view that COLEC10 inhibits HCC progression by regulating GRP78-mediated ER stress signaling and may serve as a promising therapeutic and prognostic biomarker.
收集素亚家族成员 10（COLEC10），一种主要在肝脏中表达的 C 型凝集素，参与肝细胞癌（HCC）的发展。然而，其在 HCC 进展中的潜在分子机制尚不清楚。在这项研究中，使用各种 HCC 队列验证了肿瘤组织中 COLEC10 表达减少，并与患者预后不良相关。COLEC10 过表达在体外和体内均减弱了 HCC 细胞的生长和迁移能力。我们发现 COLEC10 是 78-kDa 葡萄糖调节蛋白（GRP78）的一种新型相互作用蛋白，GRP78 是内质网（ER）中未折叠蛋白反应的主要调节剂。COLEC10 过表达增强了 HCC 细胞的 ER 应激，表现为磷酸化蛋白激酶 RNA 样内质网激酶、磷酸化肌醇需求蛋白 1α、激活转录因子 4、DNA 损伤诱导转录 3 和 X 盒结合蛋白 1s 的表达水平升高。COLEC10 过表达细胞中的 ER 也呈现扩张和碎片化的模式。从机制上讲，COLEC10 过表达通过在 ER 中直接结合 C 末端碳水化合物识别结构域增加 GRP78 占据，从而释放和激活 ER 应激传感器蛋白激酶 RNA 样内质网激酶和磷酸化肌醇需求蛋白 1α，触发未折叠蛋白反应活性。在索拉非尼处理条件下，COLEC10 过表达的 HCC 细胞产生相对较高的活性氧水平并转向凋亡细胞死亡。我们的研究首次提供了一种新的观点，即 COLEC10 通过调节 GRP78 介导的 ER 应激信号来抑制 HCC 进展，并且可能作为一种有前途的治疗和预后生物标志物。
