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Abstract
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.
Highlights
Colorectal carcinoma (CRC), as one of the most common gastrointestinal malignancies, has developed the world’s fourth most deadly cancer with a high rate of incidence and mortality [1, 2]
To determine the potential maladjustment genes involved in pyruvate metabolism, which is located in mitochondria, as shown in Table 2, we analyzed the TCGA dataset containing 50 CRC and their normal counterparts
Pyruvate translocation from the cytoplasm to the mitochondria is the first step into the TCA cycle, which needs Mitochondrial Pyruvate Carrier 1 (MPC1)/MPC2 heterodimer
Summary
Colorectal carcinoma (CRC), as one of the most common gastrointestinal malignancies, has developed the world’s fourth most deadly cancer with a high rate of incidence and mortality [1, 2]. Pyruvate was converted into lactate in cytosol despite of normoxic and hypoxic conditions in cancer cells [4] This may be due to the impaired process of pyruvate from the cytosol into the mitochondrial matrix, which is a critical metabolic step linking glycolysis and mitochondrial oxidative phosphorylation. In CRC and esophageal squamous cell carcinoma, decreased MPC1 results in accelerated aerobic glycolysis and malignant progression [11, 12]. Hypoxia-induced loss of MPC1 enhanced the expression of MMP7 and MMP9 to promote cell invasion [16]. These data suggested that MPC1 maybe serves as a suppressor to disrupt tumor malignancy. All lentiviral transfections were performed in the presence of 6 μg/ml polybrene
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