miR-125a induces apoptosis, metabolism disorder and migration impairment in pancreatic cancer cells by targeting Mfn2-related mitochondrial fission

Abstract

Mitochondrial fission is important for the development and progression of pancreatic cancer (PC). However, little is known regarding its role in pancreatic cancer apoptosis, metabolism and migration. In the current study, the mechanism by which mitochondrial fission modifies the biological characteristics of PC was explored. MicroRNA-125a (miR-125a) had the ability to inhibit mitochondrial fission and contributed to cellular survival. Suppressed mitochondrial fission led to a reduction in mitochondrial debris, preserved the mitochondrial membrane potential, inhibited mitochondrial permeability transition pore opening, ablated cytochrome c leakage into the cytoplasm and reduced the pro-apoptotic protein contents, finally blocking mitochondria related apoptosis pathways. Furthermore, defective mitochondrial fission induced by miR-125a enhanced mitochondria-dependent energy metabolism by promoting activity of electron transport chain complexes. Furthermore, suppressed mitochondrial fission also contributed to PANC-1 cell migration by preserving the F-actin balance. Furthermore, mitofusin 2 (Mfn2), the key defender of mitochondrial fission, is involved in inhibition of miR125a-mediated mitochondrial fission. Low contents of miR-125a upregulated Mfn2 transcription and expression, leading to inactivation of mitochondrial fission. Ultimately, the current study determined that miR-125a and Mfn2 are regulated by hypoxia-inducible factor 1 (HIF1). Knockdown of HIF1 reversed miR-125a expression, and therefore, inhibited Mfn2 expression, leading to activation of mitochondrial fission. Collectively, the present study demonstrated mitochondrial fission as a tumor suppression process that is regulated by the HIF/miR-125a/Mfn2 pathways, acting to restrict PANC-1 cell survival, energy metabolism and migration, with potential implications for novel approaches for PC therapy.