Abstract
Intrahepatic cholangiocarcinoma (ICC) is known to have a high malignant potential. Because of its high recurrence rate, ICC has a poor prognosis even after complete tumor resection. Compared with normal differentiated cells, cancer cells have an altered metabolism for supporting their survival in severe conditions. Cancer cells acquire additional malignant potential as a result of this metabolic alteration. Thus, the molecules known to be involved in cancer metabolism, could be novel therapeutic targets. The mitochondrial pyruvate carrier (MPC) is a recently discovered pyruvate transporter, which is located in the mitochondrial inner membrane. Although MPC is composed of two subunits, it has been reported that the MPC1 subunit is specifically associated with poor prognosis in several cancers, including colorectal and prostate cancer. However, only a few studies have assessed the clinical significance of MPC1 and the molecular mechanisms underlying its influence on cancer progression are not well understood. This study aimed to clarify the function of MPC1 that affects the malignant potential of ICC. The expression of MPC1 in ICC clinical specimens was determined by immunohistochemistry. In addition, the correlations between MPC1 expression and the survival rate, as well as various clinicopathological parameters were assessed. Low MPC1 expression correlated with poor ICC prognosis and was correlated with tumor invasion and distant metastasis. Both these phenomena are closely associated with the epithelial-mesenchymal transition (EMT). Therefore, we investigated the impact of altering the MPC1 gene expression on the malignant potential of cancer cells using biliary tract cancer cell lines invitro. The expression of MPC1 was downregulated in the cells induced to undergo EMT following treatment with TGF-β. Furthermore, the inhibition of MPC1 expression induced EMT in cancer cells, and the overexpression of MPC1 suppressed the migration of tumor cells. These results indicated that MPC1 could be a novel therapeutic target in some cancers.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy and ICC patients often have a poor prognosis
We investigated the impact of the MPC1 expression on malignant potential in ICC
The IHC results revealed that low MPC1 expression correlated with poor Recurrence-free survival (RFS) in ICC specimens and demonstrated that MPC1 expression is related to invasion and metastasis after epithelial-mesenchymal transition (EMT) induction
Summary
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy and ICC patients often have a poor prognosis. Multiple molecules and steps are involved in this metabolic alteration, for example, lactate dehydrogenase A and pyruvate kinase M2 (PKM2) play pivotal roles in aerobic glycolysis by limiting the production of pyruvate, which is essential for mitochondrial oxidative ohashi et al: MITOCHONDRIAL PYRUVATE CARRIER AND EMT phosphorylation [10,11]. Another mechanism of aerobic glycolysis, not mutually exclusive, is the inhibition of pyruvate import into the mitochondrial matrix, resulting in decreased pyruvate oxidation associated with the increase of lactate production
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