Hu Hongtao, Song Zongchang, Yao Quanjun, Geng Xiang, Jiang Li, Guo Chenyang, Li Hailiang
Department of Interventional Radiology, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, China.
Department of Radiotherapy, Zhebei Mingzhou Hospital, Huzhou, China.
Cell Physiol Biochem. 2018;47(4):1721-1728. doi: 10.1159/000491005. Epub 2018 Jul 13.
BACKGROUND/AIMS: Gastric cancer is a highly aggressive tumor containing cancer stem cells (CSCs), which participate in tumor initiation, therapeutic resistance, and tumor relapse. Proline-rich protein 11 (PRR11) has been shown to be up-regulated in human cancers; however, its role in gastric CSCs is unknown. We hypothesize that PRR11 may affect tumorigenicity of gastric CSCs. In this study, we explored the biological function and regulation of PRR11 in gastric CSCs.
Expression of PRR11 was evaluated in gastric CSC cell line by real-time quantitative PCR and western blot. The effect of PRR11 on tumorigenicity was examined by interference with gene expression using lentiviral vector-loaded shRNA. A xenograft tumor model using NOD/SCID mice was established to examine the role of PRR11 in tumor development.
Data showed that PRR11 was highly expressed in gastric CSCs. PRR11 was responsible for the maintenance of self-renewal and tumorigenicity of gastric CSCs, and overexpression of exogenous PRR11 could restore the self-renewal of gastric non-CSCs. Furthermore, interference with PRR11 altered the expression of stemness transcription factors. Interestingly, MAPK signaling controlled PRR11 expression by increasing PRR11 protein stability, and maintained gastric CSCs self-renewal in a PRR11 dependent manner.
PRR11 regulated self-renewal and tumorigenicity of gastric CSCs through MAPK signaling, and could be used as a therapeutic target for gastric cancer.
背景/目的：胃癌是一种具有高度侵袭性的肿瘤，其中包含癌症干细胞（CSCs），这些干细胞参与肿瘤的起始、治疗抵抗和肿瘤复发。富含脯氨酸蛋白11（PRR11）已被证明在人类癌症中上调；然而，其在胃癌CSCs中的作用尚不清楚。我们假设PRR11可能影响胃癌CSCs的致瘤性。在本研究中，我们探讨了PRR11在胃癌CSCs中的生物学功能及其调控机制。
通过实时定量PCR和蛋白质免疫印迹法评估PRR11在胃癌CSC细胞系中的表达。使用携带慢病毒载体的短发夹RNA干扰基因表达，以检测PRR11对致瘤性的影响。建立了使用NOD/SCID小鼠的异种移植肿瘤模型，以研究PRR11在肿瘤发展中的作用。
数据显示PRR11在胃癌CSCs中高表达。PRR11负责维持胃癌CSCs的自我更新和致瘤性，外源性PRR11的过表达可以恢复胃癌非CSCs的自我更新能力。此外，干扰PRR11会改变干性转录因子的表达。有趣的是，丝裂原活化蛋白激酶（MAPK）信号通路通过增加PRR11蛋白稳定性来控制PRR11的表达，并以PRR11依赖的方式维持胃癌CSCs的自我更新。
PRR11通过MAPK信号通路调节胃癌CSCs的自我更新和致瘤性，有望成为胃癌治疗的新靶点。
