Abstract
Reprogramming metabolism of tumor cells is a hallmark of cancer. Lactate dehydrogenase A (LDHA) is frequently overexpressed in tumor cells. Previous studies has shown higher levels of LDHA is related with colorectal cancer (CRC), but its role in tumor maintenance and underlying molecular mechanisms has not been established. Here, we investigated miRNAs-induced changes in LDHA expression. We reported that colorectal cancer express higher levels of LDHA compared with adjacent normal tissue. Knockdown of LDHA resulted in decreased lactate and ATP production, and glucose uptake. Colorectal cancer cells with knockdown of LDHA had much slower growth rate than control cells. Furthermore, we found that miR-34a, miR-34c, miR-369-3p, miR-374a, and miR-4524a/b target LDHA and regulate glycolysis in cancer cells. There is a negative correlation between these miRNAs and LDHA expression in colorectal cancer tissues. More importantly, we identified a genetic loci newly associated with increased colorectal cancer progression, rs18407893 at 11p15.4 (in 3'-UTR of LDHA), which maps to the seed sequence recognized by miR-374a. Cancer cells overexpressed miR-374a has decreased levels of LDHA compared with miR-374a-MUT (rs18407893 at 11p15.4). Taken together, these novel findings provide more therapeutic approaches to the Warburg effect and therapeutic targets of cancer energy metabolism.
Highlights
About 1, 660, 290 new cancer cases and 580, 350 cancer deaths occurred in the United States in 2013 [1]
These results suggested that higher levels Lactate dehydrogenase A (LDHA) expressed in colorectal cancer tissues plays important roles in cancer progression
Advances in understanding the biology of tumor progression and metastasis have clearly highlighted the importance of aberrant tumor metabolism, which supports tumor cells’ energy requirements and their enormous biosynthetic needs
Summary
About 1, 660, 290 new cancer cases and 580, 350 cancer deaths occurred in the United States in 2013 [1]. Most cancer cells predominantly produce energy by a high rate of glycolysis and give rise to enhanced lactate production, instead of by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria [4, 5] This preferential use of aerobic glycolysis, which is believed to initially arise as a result of a hypoxic tumor microenvironment and termed the Warburg effect, has attained a core hallmark of many cancers [4]. The microenvironment of cancer cells always be in hypoxic conditions, oxidative phosphorylation-dependent production of ATP appears secondary to the use of mitochondrial enzymes Cancer cells reprogram their metabolism, and this metabolic reprogramming in cancer cells is regulated by several oncogenic genes, including the PI3K/Akt, Myc, or hypoxiainducible factor (HIF) that serve to increase glucose uptake, glycolysis, and transcription of LDHA [6,7,8,9,10]
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