Monocarboxylate Transporter 4 Facilitates Cell Proliferation and Migration and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma Patients

Abstract

Monocarboxylate transporter 4 (MCT4) is a cell membrane transporter of lactate. Recent studies have shown that MCT4 is over-expressed in various cancers; however, its role in cancer maintenance and aggressiveness has not been fully demonstrated. This study investigated the role of MCT4 in oral squamous cell carcinoma (OSCC), and found that it is highly expressed in OSCC patients by using immunohistochemistry. Moreover, this over-expression of MCT4 was closely associated with tumor size, TNM classification, lymphatic metastasis, distant metastasis and tumor recurrence, and also poor prognosis. To further study mechanisms of MCT4 in vitro, we used small-interfering RNA to silence its expression in OSCC cell lines. The results showed that knock-down of MCT4 decreased cell proliferation, migration, and invasion. The inhibition of proliferation was associated with down-regulation of p-AKT and p-ERK1/2, while decreased cell migration and invasion may be caused by down-regulation of integrin β4-SRC-FAK and MEK-ERK signaling. Together, these findings provide new insight into the critical role of MCT4 in cell proliferation and metastasis in OSCC.

Monocarboxylate Transporters MCT1 and MCT4 Regulate Migration and Invasion of Pancreatic Ductal Adenocarcinoma Cells

“…Thus, inhibitory effects of 4-CIN on migration and invasion of highgrade glioma cells 20 and on migration of SiHa cervical cancer cells 21 have been demonstrated. Consistent with roles for these transporters in cancer cell motility in general, knockdown of MCT1 [20][21][22]24 or MCT4 23,24 was previously shown to reduce migration and/or invasion of various cancer cell lines. Until the present work, the roles of MCTs in PDAC motility were unknown.…”

“…Indeed, application of α-cyano-4-hydroxycinnamate (4-CIN), a broad-spectrum inhibitor of both MCTs and of the mitochondrial pyruvate carrier (MPC), 19 reduced migration and invasion of high-grade glioma cells, and knockdown of MCT1 reduced their migration. 20 Furthermore, 4-CIN inhibited and MCT1 overexpression stimulated the migration of SiHa cervical cancer cells 21 ; MCT1 knockdown inhibited migration and invasion of MNNG/HOS osteosarcoma cells 22 ; MCT4 knockdown inhibited migration and invasion in oral squamous cell carcinoma cell lines and in patients with oral squamous cell carcinoma, and MCT4 overexpression was associated with lymphatic and distant metastases and poor prognosis 23 ; and finally, in human lung cancer cell lines, MCT1 and MCT4 expression correlated with invasiveness and knockdown of either transporter inhibited invasiveness without affecting migration. 24 Despite the fact that the pancreatic duct exhibits an enormous capacity for acid-base transport under normal conditions 25 and that PDAC is associated with major metabolic changes, 26,27 little is known about the roles of altered acid-base transport in PDAC (for a recent review, see Ref.…”

Polymorphisms of monocarboxylate transporter genes are associated with clinical outcomes in patients with colorectal cancer

“…(Izumi et al 2011), oral squamous cell carcinoma (Zhu et al 2014) and CRC (Nakayama et al 2012;Pinheiro Fig. 2 The cumulative effects of unfavorable genotypes of MCT1 and MCT2 genes on overall (a) and recurrence-free (b) survival of CRC patients analyzed by Kaplan-Meier curves.…”

“…2 The cumulative effects of unfavorable genotypes of MCT1 and MCT2 genes on overall (a) and recurrence-free (b) survival of CRC patients analyzed by Kaplan-Meier curves. Group 1, patients with no unfavorable genotypes; Group 2, those with one unfavorable genotype; Group 3, those with two unfavorable genotypes; Group 4, those with three unfavorable genotypes (Gerlinger et al 2012;Lee et al 2012) and poor prognosis of patients (Gerlinger et al 2012;Halestrap 2013;Miranda-Goncalves et al 2013;PertegaGomes et al 2011;Zhu et al 2014). Besides MCT molecules in tumor cells, recent studies have demonstrated that MCTs expressed on tumor and stroma cells mediate a lactate shuttle, which prevent lactate accumulation in tumor microenvironment and promote the survival, proliferation and progression of cancer cells (Sanita et al 2014;Vegran et al 2011).…”

Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies

“…MCT-1 and MCT-4 have both been implicated in lactate export, although recent data suggest that MCT-4 plays the predominant role in many cancers. Much like LDH-A, several studies have demonstrated that MCT-4 expression, which is elevated in many cancers, is required for the full expression of the cancer phenotype and is associated with poor clinical outcomes [15,16,42-46]. …”