长链非编码 RNA CRART16/miR-122-5p/FOS 轴通过上调 VEGFD 表达促进胃癌血管生成。
LncRNA CRART16/miR-122-5p/FOS axis promotes angiogenesis of gastric cancer by upregulating VEGFD expression.
机构信息
Department of General Surgery, Peking University First Hospital, Beijing 100034, China.
Institute of Clinical Pharmacology, Peking University, Beijing 100034, China.
出版信息
Aging (Albany NY). 2022 May 10;14(9):4137-4157. doi: 10.18632/aging.204078.
BACKGROUND
We previously identified a novel lncRNA, CRART16, that could induce cetuximab resistance in colorectal cancer cells. This study explored the relationship of CRART16 expression to gastric cancer progression and the molecular mechanisms involved.
METHODS
We evaluated CRART16 expression in gastric cancer tissues and adjacent normal tissues from the TCGA database and our hospital. Besides, we assessed its relationship with the overall survival (OS) of patients with gastric cancer. The effects of CRART16 on gastric cancer angiogenesis were determined by endothelial tube formation assay, spheroid sprouting assay, HUVEC invasion assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the lncRNA CRART16/miR-122-5p/FOS axis was analyzed by western blotting and dual-luciferase reporter assay. The functions of CRART16 were confirmed in xenograft mouse models.
RESULTS
We found that CRART16 was substantially overexpressed in gastric cancer tissues compared with normal tissues, based on the TCGA database and our clinical samples. High expression of CRART16 correlated with more advanced tumor stages and poor prognosis. Overexpression of CRART16 in gastric cancer cells promoted proliferation, colony formation, angiogenesis, and bevacizumab resistance , and it promoted tumor growth and angiogenesis , and vice versa. CRART16 was found to downregulate miR-122-5p by acting as a sponge, upregulating the target oncogene FOS. Afterward, the increased FOS expression led to the upregulation of VEGFD.
CONCLUSION
Our findings demonstrate that CRART16 promotes angiogenesis and , and CRART16 is a prognostic marker and therapeutic target in gastric cancer.
背景
我们之前发现了一个新的长链非编码 RNA（lncRNA）CRART16，它可以诱导结直肠癌细胞对西妥昔单抗产生耐药性。本研究探讨了 CRART16 表达与胃癌进展的关系及其相关的分子机制。
方法
我们评估了 TCGA 数据库和我院胃癌组织及相邻正常组织中 CRART16 的表达情况，同时评估了其与胃癌患者总生存期（OS）的关系。通过内皮管形成试验、球体发芽试验、HUVEC 侵袭试验和鸡胚绒毛尿囊膜（CAM）试验评估了 CRART16 对胃癌血管生成的影响。通过 Western blot 和双荧光素酶报告基因实验分析了 lncRNA CRART16/miR-122-5p/FOS 轴的参与情况。通过异种移植小鼠模型验证了 CRART16 的功能。
结果
根据 TCGA 数据库和我们的临床样本，我们发现 CRART16 在胃癌组织中明显过表达，与正常组织相比。CRART16 的高表达与肿瘤分期较晚和预后不良相关。在胃癌细胞中过表达 CRART16 促进了增殖、集落形成、血管生成和贝伐珠单抗耐药性，并且促进了肿瘤生长和血管生成，反之亦然。CRART16 通过作为海绵体下调 miR-122-5p，上调靶癌基因 FOS。随后，FOS 表达的增加导致 VEGFD 的上调。
结论
我们的研究结果表明，CRART16 促进了血管生成，CRART16 是胃癌的一个预后标志物和治疗靶点。
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