Tseng Chung-Chih, Hung Chung-Ching, Shu Chih-Wen, Lee Cheng-Hsin, Chen Chun-Feng, Kuo Mei-Shu, Kao Yu-Ying, Chen Chun-Lin, Ger Luo-Ping, Liu Pei-Feng
Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
Department of Dentistry, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81342, Taiwan.
Biomedicines. 2023 Apr 25;11(5):1270. doi: 10.3390/biomedicines11051270.
There are currently no effective biomarkers for the diagnosis and treatment of tongue squamous cell carcinoma (TSCC), which causes a poor 5-year overall survival rate. Thus, it is crucial to identify more effective diagnostic/prognostic biomarkers and therapeutic targets for TSCC patients. The receptor expression-enhancing protein 6 (REEP6), a transmembrane endoplasmic reticulum resident protein, controls the expression or transport of a subset of proteins or receptors. Although it was reported that REEP6 plays a role in lung and colon cancers, its clinical impact and biological role in TSCC are still unknown. The present study aimed to identify a novel effective biomarker and therapeutic target for TSCC patients. Expression levels of REEP6 in specimens from TSCC patients were determined with immunohistochemistry. Gene knockdown was used to evaluate the effects of REEP6 in cancer malignancy (colony/tumorsphere formation, cell cycle regulation, migration, drug resistance and cancer stemness) of TSCC cells. The clinical impact of REEP6 expression and gene co-expression on prognosis were analyzed in oral cancer patients including TSCC patients from The Cancer Genome Atlas database. Tumor tissues had higher levels of REEP6 compared to normal tissues in TSCC patients. Higher REEP6 expression was related to shorter disease-free survival (DFS) in oral cancer patients with poorly differentiated tumor cells. REEP6-knocked-down TSCC cells showed diminished colony/tumorsphere formation, and they also caused G1 arrest and decreased migration, drug resistance and cancer stemness. A high co-expression of REEP6/epithelial-mesenchymal transition or cancer stemness markers also resulted in poor DFS in oral cancer patients. Thus, REEP6 is involved in the malignancy of TSCC and might serve as a potential diagnostic/prognostic biomarker and therapeutic target for TSCC patients.
目前尚无用于舌鳞状细胞癌（TSCC）诊断和治疗的有效生物标志物，这导致其5年总生存率较低。因此，为TSCC患者确定更有效的诊断/预后生物标志物和治疗靶点至关重要。受体表达增强蛋白6（REEP6）是一种跨膜内质网驻留蛋白，可控制一部分蛋白质或受体的表达或转运。尽管有报道称REEP6在肺癌和结肠癌中发挥作用，但其在TSCC中的临床影响和生物学作用仍不清楚。本研究旨在为TSCC患者确定一种新的有效生物标志物和治疗靶点。采用免疫组织化学法测定TSCC患者标本中REEP6的表达水平。利用基因敲低技术评估REEP6对TSCC细胞癌症恶性程度（集落/肿瘤球形成、细胞周期调控、迁移、耐药性和癌症干性）的影响。对包括来自癌症基因组图谱数据库的TSCC患者在内的口腔癌患者，分析REEP6表达和基因共表达对预后的临床影响。与TSCC患者的正常组织相比，肿瘤组织中REEP6水平更高。在肿瘤细胞分化差的口腔癌患者中，较高的REEP6表达与较短的无病生存期（DFS）相关。REEP6基因敲低的TSCC细胞显示集落/肿瘤球形成减少，同时还导致G1期阻滞，并降低迁移、耐药性和癌症干性。REEP6/上皮-间质转化或癌症干性标志物的高共表达也导致口腔癌患者DFS较差。因此，REEP6参与了TSCC的恶性进程，可能作为TSCC患者潜在的诊断/预后生物标志物和治疗靶点。
