MiR-21-mediated Metabolic Alteration of Cancer-associated Fibroblasts and Its Effect on Pancreatic Cancer Cell Behavior

• Published in: International journal of biological sciences Vol. 14; no. 1; pp. 100 - 110
• Main Authors: Chen, Shuo, Chen, Xi, Shan, Tao, Ma, Jiancang, Lin, Wanrun, Li, Wei, Kang, Ya'an
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01-01-2018; Ivyspring International Publisher
• Subjects: Acid production; Aerobic capacity; Cancer; Cancer-Associated Fibroblasts - metabolism; Cell culture; Cell Line, Tumor; Fibroblasts; Fumarase; Gene Expression Regulation, Neoplastic - genetics; Gene Expression Regulation, Neoplastic - physiology; Glucose; Glycolysis; Glycolysis - genetics; Glycolysis - physiology; Humans; Immunohistochemistry; Inhibitors; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - genetics; L-Lactate Dehydrogenase - metabolism; Lactate dehydrogenase; Lactic acid; Metabolism; MicroRNAs - genetics; MicroRNAs - metabolism; Oxidation; Oxidative phosphorylation; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phosphorylation; Pyruvate kinase; Pyruvic acid; Research Paper; cancer-associated fibroblasts; metabolic alteration; miR-21; glycolysis
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.22555

In this study, we investigated whether the metabolic alteration of
(CAFs) occurs via miR-21 remodeling and the effect of this alteration on pancreatic cancer cells. CAFs and normal fibroblasts (NFs) were isolated and cultured. Glucose consumption and lactic acid production were tested, and lactate dehydrogenase (LDHA), pyruvate kinase m2 (PKM2), and miR-21 expression were examined. The level of glycolysis in CAFs was determined after treatment with a miR-21 inhibitor. Primary miR-21-NC CAFs and miR-21-inhibitor CAFs were indirectly co-cultured with BxPc-3
, and the invasion capacity of these cells was determined. The aerobic oxidation index of cancer cells and the expression of succinodehydrogenase (SDH) and fumarate hydratase (FH) were assessed. Compared with NFs, CAFs showed enhanced glucose uptake capacity, lactic acid production, and elevated LDHA, PKM2, and miR-21 expression. After miR-21 inhibitor treatment, the extent of glycolysis in CAFs was reduced. After indirect co-culture with CAFs, oxidative phosphorylation and SDH, FH, and MCT expression increased in BxPc-3 cells. After co-culture with miR-21-inhibitor-CAFs, oxidative phosphorylation and invasion ability of the pancreatic cancer cells decreased. MiR-21 was involved in metabolic alteration of CAFs and affected the development of cancer cells. This metabolic alteration may be an important mechanism by which the microenvironment promotes tumor progression in a nonvascular manner.