Wei Sisi, Fan Xinyi, Li Xiaoya, Zhou Wei, Zhang Zhihua, Dai Suli, Lv Huilai, Liu Yueping, Shan Baoen, Zhao Lianmei, Zhan Qimin, Song Yongmei
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Research Center, the Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, Hebei, 050011, China.
Adv Sci (Weinh). 2025 Jan;12(4):e2406674. doi: 10.1002/advs.202406674. Epub 2024 Dec 4.
Hypoxia is a typical hallmark of solid tumors and plays a crucial role in the progression of esophageal squamous cell carcinogenesis (ESCC). Nevertheless, the precise mechanisms underlying the involvement of hypoxia in tumor development remain unclear. In the present study, a novel hypoxia-induced long noncoding RNA (lncRNA) is identified first, lnc191, which is highly expressed in clinical ESCC tissues and is positively correlated with poor prognosis of ESCC patients. These findings provide evidence that the hypoxia-inducible factor-1α (HIF-1α)-mediated transcriptional activation of lnc191 enhances the growth and metastasis of ESCC cells both in vitro and in vivo. Mechanistically, lnc191 interacts with GRP78 (78-kDa glucose-regulated protein), one of the endoplasmic reticulum chaperone proteins, leading to its translocation to the membrane, where GRP78 binds with EGFR and enhances its phosphorylation (Y845), further activates ERK/MAPK signaling pathway, and thereby in favor of the progression of ESCC. Overall, this data proposes lnc191 as a key driver during the development of ESCC and reveals the participation of the activated GRP78/ERK/MAPK axis in the ESCC progression mediated by lnc191. These findings indicate the potential of lnc191 as a promising diagnostic biomarker and therapeutic target in ESCC.
缺氧是实体瘤的典型特征，在食管鳞状细胞癌（ESCC）发生发展过程中起关键作用。然而，缺氧参与肿瘤发展的精确机制仍不清楚。在本研究中，首先鉴定出一种新的缺氧诱导长链非编码RNA（lncRNA），即lnc191，其在临床ESCC组织中高表达，且与ESCC患者的不良预后呈正相关。这些发现表明，缺氧诱导因子-1α（HIF-1α）介导的lnc191转录激活在体外和体内均增强了ESCC细胞的生长和转移。机制上，lnc191与内质网伴侣蛋白之一的GRP78（78 kDa葡萄糖调节蛋白）相互作用，导致其转运至细胞膜，在那里GRP78与EGFR结合并增强其磷酸化（Y845），进一步激活ERK/MAPK信号通路，从而促进ESCC的进展。总体而言，这些数据表明lnc191是ESCC发展过程中的关键驱动因素，并揭示了激活的GRP78/ERK/MAPK轴参与lnc191介导的ESCC进展。这些发现表明lnc191作为ESCC中有前景的诊断生物标志物和治疗靶点的潜力。
