ABSTRACT
Metabolic reprogramming is a malignant phenotype of cancer. Cancer cells utilize glycolysis to fuel rapid proliferation even in the presence of oxygen, and elevated glycolysis is coupled to lactate fermentation in the cancer microenvironment. Although lactate has been recognized as a metabolic waste product, it has become evident that lactate functions as not only an energy source but a signaling molecule through the lactate receptor G-protein-coupled receptor 81 (GPR81) under physiological conditions. However, the pathological role of GPR81 in cancer remains unclear. Here, we show that GPR81 regulates the malignant phenotype of breast cancer cell by reprogramming energy metabolism. We found that GPR81 is highly expressed in breast cancer cell lines but not in normal breast epithelial cells. Knockdown of GPR81 decreased breast cancer cell proliferation, and tumor growth. Mechanistically, glycolysis and lactate-dependent ATP production were impaired in GPR81-silenced breast cancer cells. RNA sequencing accompanied by Gene Ontology enrichment analysis further demonstrated a significant decrease in genes associated with cell motility and silencing of GPR81 suppressed cell migration and invasion. Notably, histological examination showed strong expression of GPR81 in clinical samples of human breast cancer. Collectively, our findings suggest that GPR81 is critical for malignancy of breast cancer and may be a potential novel therapeutic target for breast carcinoma.
Subject(s)
Breast Neoplasms , Lactic Acid , Receptors, G-Protein-Coupled , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Glycolysis , Humans , Lactic Acid/metabolism , Receptors, G-Protein-Coupled/metabolism , Tumor MicroenvironmentABSTRACT
Endochondral bone formation is fundamental for skeletal development. During this process, chondrocytes undergo multiple steps of differentiation and coordinated transition from a proliferating to a hypertrophic stage, which is critical to advance skeletal development. Here, we identified the transcription factor Dmrt2 (double-sex and mab-3 related transcription factor 2) as a Sox9-inducible gene that promotes chondrocyte hypertrophy in pre-hypertrophic chondrocytes. Epigenetic analysis further demonstrated that Sox9 regulates Dmrt2 expression through an active enhancer located 18 kb upstream of the Dmrt2 gene and that this enhancer's chromatin status is progressively activated through chondrocyte differentiation. Dmrt2-knockout mice exhibited a dwarf phenotype with delayed initiation of chondrocyte hypertrophy. Dmrt2 augmented hypertrophic chondrocyte gene expression including Ihh through physical and functional interaction with Runx2. Furthermore, Dmrt2 deficiency reduced Runx2-dependent Ihh expression. Our findings suggest that Dmrt2 is critical for sequential chondrocyte differentiation during endochondral bone formation and coordinates the transcriptional network between Sox9 and Runx2.
Subject(s)
Bone and Bones/metabolism , Chondrocytes/metabolism , Core Binding Factor Alpha 1 Subunit/metabolism , DNA-Binding Proteins/metabolism , Dwarfism/metabolism , Osteogenesis , SOX9 Transcription Factor/metabolism , Transcription Factors/metabolism , Animals , Bone and Bones/pathology , Bone and Bones/physiopathology , Cell Line, Tumor , Chondrocytes/pathology , Chondrogenesis , Core Binding Factor Alpha 1 Subunit/genetics , DNA-Binding Proteins/genetics , Disease Models, Animal , Dwarfism/genetics , Dwarfism/pathology , Dwarfism/physiopathology , Epigenesis, Genetic , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Hypertrophy , Mice, Inbred C57BL , Mice, Knockout , SOX9 Transcription Factor/genetics , Signal Transduction , Transcription Factors/genetics , Transcription, GeneticABSTRACT
Herein, an ultrahigh 18-fold expansion of isotactic polypropylene (iPP)/cellulose nanofiber (CNF) nanocomposite foams was achieved for the first time using a core-back foam injection molding technique. It was found that CNFs were well dispersed and aligned along the cell wall in the core-back direction. Interestingly, the formations of a hybrid shish-kebab of CNFs and classic shish-kebab of PP were simultaneously achieved in the PP/CNF composites. Finally, we proposed that the combination of local strong melt strength, probably resulting from the strong alignment of CNFs and subsequent formation of hybrid shish-kebab structures, and weak melt strength in the unreinforced PP melt might be the driving force for remarkably enhancing the PP foamability.