The role of phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) in regulating the progression of oral squamous cell carcinoma.

OBJECTIVE: The aim of this study was to explore the role of the tumor suppressor phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) on oral squamous cell carcinoma (OSCC) and its molecular mechanism. DESIGN: Immunohistochemistry detected the expression of PAG1 in normal and tumor tissues. The PAG1 overexpressed OSCC cell lines were constructed by lentivirus transfection. Cell Counting Kit-8 assay (CCK-8), clone formation and flow cytometry evaluated the impact of PAG1 on the proliferation and apoptosis of OSCC cells. RNA sequencing (RNA-seq) detected the changes in intracellular genes, and transmission electron microscope (TEM) was used to compare the number of autophagosomes in OSCC cells between Negative and PAG1 group. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blot were used to determine the expression of signaling pathway-related mRNA and proteins respectively. RESULTS: In contrast to the normal tissues, PAG1 expression was significantly downregulated in tumor tissues. Treatment with lentivirus transfection, the expression of PAG1 in the OSCC cell lines was increase. Notably, transfected with PAG1-overexpressing lentivirus cells inhibited the proliferation of OSCC cells and promoted OSCC cells apoptosis. RNA-seq revealed that PAG1 mainly modulated the mitophagy and autophagy pathway, and many autophagosomes were observed in the PAG1 group using TEM. Mechanistically, we found that PAG1 upregulated the expression of autophagy related factors through inhibiting PI3K/Akt/mTOR signal pathway activation. CONCLUSION: Overexpression of PAG1 inhibited OSCC progression by activating autophagy, its mechanism might be related to inhibition of PI3K/Akt/mTOR signal pathway phosphorylation.

Low-molecular-weight fucoidan bidirectionally regulates lipid uptake and cholesterol efflux through the p38 MAPK phosphorylation.

Atherosclerosis (AS) is the pathological basis of many cardiovascular and cerebrovascular diseases, in which macrophage-derived foam cells are the critical step and a typical pathological feature of early atherosclerosis. We previously confirmed that low-molecular-weight fucoidan (LMWF) had a good anti-AS effect, but the mechanism is still unclear. Here with aim to investigate the inhibitory effect of LMWF on foam cells and its molecular mechanism. Oil red O staining showed that LMWF effectively alleviated lipid accumulation and the formation of foam cells. Flow cytometry detection showed that LMWF promoted foam cells apoptosis. In addition, immunofluorescence showed that LMWF inhibited macrophage scavenger receptor A1 (SR-A1)-mediated lipid uptake and promoted ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol outflow. Western blot showed that LMWF downregulated SR-A1 protein expression and upregulated ABCA1 protein expression by inhibiting p38 mitogen activated protein kinase (p38MAPK) phosphorylation. Moreover, the mRNA transcriptions of Stat1, Elk-1, and Myc were downregulated when treated with LMWF. It concluded that, LMWF achieved bidirectional regulation of SR-A1 and ABCA1, then prevented the formation of foam cells, finally ameliorated the development of AS.