Acidic Tumor Microenvironment Promotes Pancreatic Cancer through miR-451a/MEF2D Axis

Pancreatic cancer (PC), as a highly malignant and aggressive solid tumor, is common in the digestive system. The acidic microenvironment is one of the critical markers of cancer. Nonetheless, there are few studies on how the acidic microenvironment affects the development of PC. This study focused on investigating the specific molecular mechanisms of the acidic microenvironment in PC. In our study, qRT-PCR was conducted for examining microRNA (miR)-451a and myocyte enhancer factor 2D (MEF2D) expressions in PANC-1 cells. Then, detailed functional effects of an acidic environment on miR-451a and MEF2D in PANC-1 cells were detected by CCK-8, colony formation, flow cytometry, wound healing, transwell, mitochondrial functionality measurement, JC-1 staining, DCFH-DA staining, and sphere formation assays. The relationship between miR-451a and MEF2D was confirmed by luciferase reporter analysis. Under acidic conditions, the increase of proliferation, migration, and invasion of PANC-1 cells was observed. Moreover, the mitochondrial oxidative respiration-related gene miR-451a was reduced in acidic conditions. In addition, we found that, in PANC-1 cells under an acidic environment, miR-451a overexpression enhanced oxygen consumption, mitochondrial membrane potential (MMP) loss, and ROS generation and inhibited proliferation, migration, invasion, and stemness via sponging MEF2D. In a word, our results revealed that the acidic microenvironment regulated PC progression by affecting the miR-451a/MEF2D axis, indicating a novel avenue for the future treatment of PC.

Automated summary

This study investigated the molecular mechanisms of the acidic microenvironment in pancreatic cancer (PC) progression. It was found that under acidic conditions, PANC-1 cells exhibited increased proliferation, migration, and invasion. Additionally, the expression of miR-451a, a gene related to mitochondrial oxidative respiration, was reduced in acidic conditions. Overexpression of miR-451a inhibited proliferation, migration, invasion, and stemness of PANC-1 cells under an acidic environment by targeting MEF2D. These findings provide a novel avenue for the future treatment of PC.