Rationale:
MicroRNAs are known to influence the development of a variety of
cancers. Previous studies revealed that miR-1291 has antiproliferative functions in
cancer cells.
Carnitine palmitoyltransferase 1C (CPT1C) has a vital role in mitochondrial energy metabolism and modulation of
cancer cell proliferation. Since both miR-1291 and CPT1C regulate
tumor cell metabolism and
cancer progression, we hypothesized that they might be regulated synergistically. Methods: A series of cell phenotype indicators, such as
BrdU, colony formation, cell cycle,
ATP production, ROS accumulation and cell ability to resist metabolic stress, were performed to clarify the effects of miR-1291 and ERRα expression on
tumor cell proliferation and metabolism. A xenograft
tumor model was used to evaluate cell
tumorigenesis. Meta-analysis and bioinformatic prediction were applied in the search for the bridge-link between miR-1291 and CPT1C. RT-qPCR, western-blot and IHC analysis were used for the detection of
mRNA and
protein expression.
Luciferase assays and ChIP assays were conducted for in-depth mechanism studies. Results: The expression of miR-1291 inhibited growth and
tumorigenesis as a result of modulation of metabolism. CPT1C expression was indirectly and negatively correlated with miR-1291 levels. ESRRA was identified as a prominent differentially expressed gene in both breast and
pancreatic cancer samples, and
estrogen-related receptor α (ERRα) was found to link miR-1291 and CPT1C. MiR-1291 targeted ERRα and CPT1C was identified as a newly described ERRα target gene. Moreover, ERRα was found to influence
cancer cell metabolism and proliferation, consistent with the cellular changes caused by miR-1291. Conclusion: This study demonstrated the existence and mechanism of action of a novel miR-1291-ERRα-CPT1C
cancer metabolism axis that may provide new insights and strategies for the development of
miRNA-based
therapies for malignant
cancers.