Ma Xiaobin, Yan Wenyu, Xu Peng, Ma Li, Zan Ying, Huang Lanxuan, Wang Guanying, Liu Lili, Hui Wentao
Department of Oncology, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, No. 157 Xiwu Road, Xi'an 710004, Shaanxi, China.
Biol Chem. 2022 Aug 11;403(10):945-958. doi: 10.1515/hsz-2022-0153. Print 2022 Sep 27.
The long non-coding RNA p21 (lncRNA-p21) was a tumor suppressor gene in most cancer types including gastric cancer (GC). We aimed to identify a specific lncRNA-p21-involved pathway in regulating the proliferation and apoptosis of GC cells. A lower lncRNA-p21 expression in tumors was associated with advanced disease stage and predicted worse survival of GC patients. LncRNA-p21 overexpression in GC cell line somatic gastric cancer (SGC)-7901 and human gastric cancer (HGC)-27 suppressed cell proliferation and enhanced apoptosis, while lncRNA-p21 knockdown caused the opposite effects. Through bioinformatics analysis and luciferase-based reporter assays, we identified miR-514b-3p as a sponge target of lncRNA-p21. Cdc42 guanine nucleotide exchange factor 9 (ARHGEF9), functioned as a tumor suppress factor in GC, was found as the downstream target of miR-514-3p, and their expressions were negatively correlated in GC tumor tissues. In addition, like lncRNA-p21 overexpression alone, miR-514-3p inactivation alone also led to decreased proliferation and increased apoptosis in SGC-7901 and HGC-27 cells, which were markedly attenuated by additional ARHGEF9 knockdown. Xenograft SGC-7901 cells with more lncRNA-p21 or ARHGEF9 expressions or with less miR-514-3p expression exhibited obviously slower growth than the control SGC-7901 cells in nude mice. Our study reveals a novel lncRNA-p21/miR-514b-3p/ARHGEF9 pathway that can be targeted for GC therapy.
长链非编码RNA p21（lncRNA-p21）在包括胃癌（GC）在内的大多数癌症类型中是一种肿瘤抑制基因。我们旨在确定lncRNA-p21参与调节GC细胞增殖和凋亡的特定途径。肿瘤中lncRNA-p21表达较低与疾病晚期相关，并预示GC患者的生存率较差。GC细胞系人胃癌（SGC）-7901和人胃癌（HGC）-27中lncRNA-p21的过表达抑制细胞增殖并增强凋亡，而lncRNA-p21的敲低则产生相反的效果。通过生物信息学分析和基于荧光素酶的报告基因检测，我们确定miR-514b-3p是lncRNA-p21的海绵靶点。鸟嘌呤核苷酸交换因子9（ARHGEF9）在GC中作为肿瘤抑制因子发挥作用，被发现是miR-514-3p的下游靶点，并且它们在GC肿瘤组织中的表达呈负相关。此外，与单独过表达lncRNA-p21一样，单独使miR-514-3p失活也导致SGC-7901和HGC-27细胞增殖减少和凋亡增加，而额外敲低ARHGEF9则明显减弱了这些作用。在裸鼠中，具有更多lncRNA-p21或ARHGEF9表达或更少miR-514-3p表达的异种移植SGC-7901细胞的生长明显比对照SGC-7901细胞慢。我们的研究揭示了一种可用于GC治疗的新型lncRNA-p21/miR-514b-3p/ARHGEF9途径。
