Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer.

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.

• Authors: Jian Wang, Hui Wang, Aifen Liu, Changge Fang, Jianguo Hao, Zhenghui Wang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 23 Pg. 19456-68 (Aug 14 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26062441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• Isoenzymes
• MicroRNAs
• Lactic Acid
• Adenosine Triphosphate
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5

Topics

• 3' Untranslated Regions
• Adenosine Triphosphate (metabolism)
• Animals
• Binding Sites
• Cell Proliferation
• Colorectal Neoplasms (enzymology, genetics, pathology)
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Glycolysis
• HCT116 Cells
• HT29 Cells
• Humans
• Isoenzymes (genetics, metabolism)
• L-Lactate Dehydrogenase (genetics, metabolism)
• Lactate Dehydrogenase 5
• Lactic Acid (metabolism)
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• RNA Interference
• Signal Transduction
• Time Factors
• Transfection
• Tumor Burden
• Up-Regulation