title: 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.affiliation: Intensive Care Unit, Tianjin Hospital, Tianjin, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Tianjin Public Security Hospital, Tianjin, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, The Second Hospital Affiliated to Tianjin Medical University, Tianjin, China.
authors.forename: Aifen
authors.initials: A
authors.lastname: Liu
authors.affiliation: Advanced Personalized Diagnostics LLC, Alexandria, VA, USA.
authors.forename: Changge
authors.initials: C
authors.lastname: Fang
authors.affiliation: Department of General Surgery, Taiyuan Central Hospital, Shanxi, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Anatomy, Histology and Embryology, Logistics University of CAPF, Tianjin, China.
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006019:Glycolysis; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000378:metabolism; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D007527:Isoenzymes; D035683:MicroRNAs; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5
keywords: 3’untranslated region; Warburg effect; colorectal cancer; lactate dehydrogenase A; miRNA