Yang Jigang, Guo Feihu, Yuan Leilei, Lv Guangxin, Gong Jianhua, Chen Jing
Nuclear Medicine Department, Beijing Friendship Hospital, Affiliated to Capital Medical University, Beijing, China.
R&D Department, High Tech of Atom Co Ltd, Beijing, China.
J Cell Biochem. 2019 Jul;120(7):11690-11701. doi: 10.1002/jcb.28448. Epub 2019 Feb 11.
Mutations of the Ras oncogene are frequently detected in human cancers. Among Ras-mediated tumorigenesis, Kras-driven cancers are the most dominant mutation types. Here, we investigated molecular markers related to the Kras mutation, which is involved in energy metabolism in Kras mutant-driven cancer. We first generated a knock-in Kras cell line as a model. The genotype and phenotype of the Kras -driven cells were first confirmed. Dramatically elevated metabolite characterization was observed in Kras -driven cells compared with wild-type cells. Analysis of mitochondrial metabolite-related genes showed that two of the 84 genes in Kras -driven cells differed from control cells by at least twofold. The messenger RNA and protein levels of ATP6V0D2 were significantly upregulated in Kras -driven cells. Knockdown of ATP6V0D2 expression inhibited motility and invasion but did not affect the proliferation of Kras -driven cells. We further investigated ATP6V0D2 expression in tumor tissue microarrays. ATP6V0D2 overexpression was observed in most carcinoma tissues, such as melanoma, pancreas, and kidney. Thus, we suggest that ATP6V0D2, as one of the V-ATPase (vacuolar-type H -ATPase) subunit isoforms, may be a potential therapeutic target for Kras mutation cancer.
Ras癌基因的突变在人类癌症中经常被检测到。在Ras介导的肿瘤发生过程中，Kras驱动的癌症是最主要的突变类型。在此，我们研究了与Kras突变相关的分子标志物，该突变参与Kras突变驱动的癌症中的能量代谢。我们首先构建了一个敲入Kras细胞系作为模型。首先确认了Kras驱动细胞的基因型和表型。与野生型细胞相比，在Kras驱动的细胞中观察到代谢物特征显著升高。对线粒体代谢物相关基因的分析表明，Kras驱动细胞中84个基因中的两个与对照细胞相比至少相差两倍。ATP6V0D2的信使核糖核酸和蛋白质水平在Kras驱动的细胞中显著上调。敲低ATP6V0D2表达可抑制Kras驱动细胞的运动性和侵袭性，但不影响其增殖。我们进一步研究了肿瘤组织微阵列中ATP6V0D2的表达。在大多数癌组织中观察到ATP6V0D2过表达，如黑色素瘤、胰腺和肾脏。因此，我们认为ATP6V0D2作为V-ATP酶（液泡型H -ATP酶）亚基异构体之一，可能是Kras突变癌症的潜在治疗靶点。
