CA9Silencing Promotes Mitochondrial Biogenesis, Increases Putrescine Toxicity and Decreases Cell Motility to Suppress ccRCC Progression
CA9Silencing Promotes Mitochondrial Biogenesis, Increases Putrescine Toxicity and Decreases Cell Motility to Suppress ccRCC Progression
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CA9沉默促进线粒体生物发生、增加腐胺毒性并降低细胞运动性以抑制 ccRCC 进展
DOI：
10.3390/ijms21165939
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发表时间：
2020
影响因子：
5.6
通讯作者：
Deng Haiteng
中科院分区：
文献类型：
--
作者：
Xu Jiatong;Zhu Songbiao;Xu Lina;Liu Xiaohui;Ding Wenxi;Wang Qingtao;Chen Yuling;Deng Haiteng
碳酸酐酶IX （CA9）是一种ph调节跨膜蛋白，在实体瘤中高度表达，特别是在透明细胞肾细胞癌（ccRCC）中。CA9的催化机制已被明确，但其在ccRCC中介导细胞迁移/入侵和存活的作用仍有待确定。在这里，我们通过对the Cancer Genome Atlas数据集的分析，证实了ca9在ccRCC中的mRNA表达明显高于癌旁组织。ca9敲低上调氧化磷酸化相关蛋白，增加线粒体生物发生，导致Warburg表型逆转和细胞生长抑制。我们的研究表明，ca9的下调上调了线粒体精氨酸酶2 (ARG2)，导致腐胺的积累，从而抑制了ccRCC的增殖。表面组学分析显示，ca9敲低下调了与细胞外基质（ECM）受体相互作用和细胞粘附相关的蛋白，导致细胞迁移减少。ca9沉默也下调氨基酸转运蛋白，导致细胞氨基酸减少。总的来说，我们的数据表明，CA9敲低通过代谢重编程和减少细胞迁移来抑制增殖，重申CA9是ccRCC治疗的潜在治疗靶点。
Carbonic anhydrase IX (CA9), a pH-regulating transmembrane protein, is highly expressed in solid tumors, and particularly in clear cell renal cell carcinoma (ccRCC). The catalytic mechanisms of CA9 are well defined, but its roles in mediating cell migration/invasion and survival in ccRCC remain to be determined. Here, we confirmed that the mRNA expression ofCA9in ccRCC was significantly higher than that in para-carcinoma tissues from analysis of the datasets in The Cancer Genome Atlas.CA9knockdown upregulated oxidative phosphorylation-associated proteins and increased mitochondrial biogenesis, resulting in the reversal of the Warburg phenotype and the inhibition of cell growth. Our study revealed thatCA9knockdown upregulated mitochondrial arginase 2 (ARG2), leading to the accumulation of putrescine, which suppressed ccRCC proliferation. Surfaceomics analysis revealed thatCA9knockdown downregulated proteins associated with extracellular matrix (ECM)-receptor interaction and cell adhesion, resulting in decreased cell migration.CA9silencing also downregulated amino acid transporters, leading to reduced cellular amino acids. Collectively, our data show thatCA9knockdown suppresses proliferation via metabolic reprogramming and reduced cell migration, reaffirming that CA9 is a potential therapeutic target for ccRCC treatment.