Abstract
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.
Highlights
Pancreatic cancer (PC), as the most common malignant solid tumor of the digestive system, is characterized by high malignancy and invasiveness, and poor prognosis, with less than 8% 5-year survival rate, which is one of the greatest challenges in modern oncology research [1,2,3]
The generation of an acidic microenvironment induced with tumors including PC can inhibit tumor cell apoptosis and promote cell proliferation, invasion, and immune escape [7, 14]. us, whether the Journal of Oncology acidic microenvironment contributes to the progression of PC aroused our concern
Myocyte enhancer factor 2D (MEF2D), a member of the MEF2 family exhibiting functional effects on the progression of tumors including PC [21], might be a potential target of miR-451a according to bioinformatics prediction. erefore, whether miR-451a regulates the proliferation, migration, invasion, and apoptosis of PC cells through myocyte enhancer factor 2D (MEF2D) under an acidic microenvironment was investigated in this study
Summary
Pancreatic cancer (PC), as the most common malignant solid tumor of the digestive system, is characterized by high malignancy and invasiveness, and poor prognosis, with less than 8% 5-year survival rate, which is one of the greatest challenges in modern oncology research [1,2,3]. MiRNAs have been found to possess substantial impacts on cell activities, such as proliferation, differentiation, and apoptosis and are involved in the progression of most malignant tumors, including PC [16, 17]. Clarence et al reported that miR-451a as a tumor suppressor was downregulated in the hypopharyngeal carcinogenesis exposure to weakly acidic bile [20]. Among those dysregulating miRNAs in the acidic microenvironment, miR-451a, as an attractive candidate, was low expressed under acidic conditions. Erefore, whether miR-451a regulates the proliferation, migration, invasion, and apoptosis of PC cells through MEF2D under an acidic microenvironment was investigated in this study Myocyte enhancer factor 2D (MEF2D), a member of the MEF2 family exhibiting functional effects on the progression of tumors including PC [21], might be a potential target of miR-451a according to bioinformatics prediction. erefore, whether miR-451a regulates the proliferation, migration, invasion, and apoptosis of PC cells through MEF2D under an acidic microenvironment was investigated in this study
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