Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer
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Jian Wang1,*, Hui Wang2,*, Aifen Liu3, Changge Fang4, Jianguo Hao5, Zhenghui Wang6
1Intensive Care Unit, Tianjin Hospital, Tianjin, China
2Department of General Surgery, Tianjin Public Security Hospital, Tianjin, China
3Department of Anesthesiology, The Second Hospital Affiliated to Tianjin Medical University, Tianjin, China
4Advanced Personalized Diagnostics LLC, Alexandria, VA, USA
5Department of General Surgery, Taiyuan Central Hospital, Shanxi, China
6Department of Anatomy, Histology and Embryology, Logistics University of CAPF, Tianjin, China
*These authors have contributed equally to this work
Zhenghui Wang, e-mail: [email protected]
Keywords: lactate dehydrogenase A, miRNA, 3’untranslated region, warburg effect, colorectal cancer
Received: December 29, 2014 Accepted: February 08, 2015 Published: April 10, 2015
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.
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