MPC1 Deficiency Promotes CRC Liver Metastasis via Facilitating Nuclear Translocation of β-Catenin
MPC1 Deficiency Promotes CRC Liver Metastasis via Facilitating Nuclear Translocation of β-Catenin
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DOI：
10.1155/2020/8340329
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发表时间：
2020-08
影响因子：
4.1
通讯作者：
Guangang Tian;Chunjie Xu;Kai-Xia Zhou;Zhi-gang Zhang;J. Gu;Xueli Zhang;Ya-Hui Wang
中科院分区：
文献类型：
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作者：
Guangang Tian;Chunjie Xu;Kai-Xia Zhou;Zhi-gang Zhang;J. Gu;Xueli Zhang;Ya-Hui Wang
越来越多的证据表明，转移是包括结直肠癌在内的多种恶性肿瘤死亡的主要原因。在结直肠癌发生过程中，转移能力与重编程的能量代谢密切相关。线粒体丙酮酸载体1（mitochondrialPyruvateCarrier 1，MPC 1）作为丙酮酸进入线粒体的载体，连接糖酵解和TCA循环，影响能量的产生。然而，MPC 1在CRC肿瘤转移中的具体作用仍未探索。在这里，通过使用TCGA数据集对参与丙酮酸代谢的基因进行数据挖掘，我们发现与非肿瘤组织相比，MPC 1在CRC中显著下调。在多个GEO数据集中也发现了类似的MPC 1表达模式。在人样品和AOM/DSS诱导的小鼠CRC模型中的IHC染色均显示MPC 1的显著下调。此外，我们发现MPC 1在正常组织、原发性结直肠癌和转移性结直肠癌中的表达逐渐降低。此外，MPC 1低表达的患者预后不良，尤其是有转移的患者。随后，功能测试表明，MPC 1过表达抑制CRC细胞的运动在体外和MPC 1沉默增强肝转移在体内。此外，我们发现减少的MPC 1通过促进β-catenin的核转位来介导MMP 7、E-cadherin、Snail 1和myc的表达，从而激活Wnt/β-catenin通路。总的来说，我们的数据表明MPC 1有潜力成为CRC诊断和治疗靶点的有希望的生物标志物。
Accumulating evidence has pointed out that metastasis is the leading cause of death in several malignant tumor, including CRC. During CRC, metastatic capacity is closely correlated with reprogrammed energy metabolism. Mitochondrial Pyruvate Carrier 1 (MPC1), as the carrier of transporting pyruvate into mitochondria, linked the glycolysis and TCA cycle, which would affect the energy production. However, the specific role of MPC1 on tumor metastasis in CRC remains unexplored. Here, by data mining of genes involved in pyruvate metabolism using the TCGA dataset, we found that MPC1 was significantly downregulated in CRC compared to nontumor tissues. Similar MPC1 expression pattern was also found in multiple GEO datasets. IHC staining in both human sample and AOM/DSS induced mouse CRC model revealed significant downregulation of MPC1. What is more, we found that MPC1 expression was gradually decreased in normal tissue, primary CRC, and metastasis CRC. Additionally, poor prognosis emerged in the MPC1 low expression patients, especially in patients with metastasis. Following, functional tests showed that MPC1 overexpression inhibited the motility of CRC cells in vitro and MPC1 silencing enhanced liver metastases in vivo. Furthermore, we uncovered that decreased MPC1 activated the Wnt/β-catenin pathway by promoting nuclear translocation of β-catenin to mediate the expression of MMP7, E-cadherin, Snail1, and myc. Collectively, our data suggest that MPC1 has the potential to be served as a promising biomarker for diagnosis and a therapeutic target in CRC.