PAGE5调控PI3K/AKT/MMP1轴促进乳腺癌侵袭和肝转移OA

[Objective]This study aimed to elucidate the specific molecular mechanism by which PAGE5 promotes breast cancer cell invasion and hepatic metastasis through regulating the PI3K/AKT signaling pathway and its downstream effector,matrix metalloproteinase 1(MMP1).[Methods]Bioinformatics analysis using the TCGA database was performed to evaluate PAGE5 expression in metastatic breast cancer tissues.The effects of PAGE5 on the proliferation,migration,and invasion capabilities of breast cancer cells were analyzed using CCK-8,EdU,Transwell,and wound healing assays.A splenic injection hepatic metastasis model in NOD-SCID mice was employed to validate the impact of PAGE5 on breast cancer liver metastasis.Transcriptome sequencing and KEGG enrichment analysis were conducted to identify potential signaling pathways regulated by PAGE5.Western blot was used to detect AKT phosphorylation levels.Quantitative real-time polymerase chain reaction(qPCR)was applied to screen and validate downstream target molecules of PAGE5.[Results]Bioinformatic analysis revealed that PAGE5 expression was significantly upregulated in distant metastasis of breast cancer.Both in vitro and in vivo experiments confirmed that PAGE5 overexpression markedly enhanced the migration and invasion abilities of breast cancer cells and promoted the formation of liver metastatic lesions,whereas PAGE5 knockdown suppressed breast cancer liver metastasis(P<0.000 1).Transcriptome sequencing and KEGG enrichment analysis indicated that PAGE5 significantly activated the PI3K-AKT signaling pathway(P=0.028 5).Western blot confirmed that PAGE5 upregulated p-AKT levels,which could be reversed by MK2206.The qPCR results confirmed that MMP1 is a key downstream effector of PAGE5,and its expression can be inhibited by MK2206(P<0.000 1).[Conclusions]This study preliminarily demonstrates that PAGE5 can activate the PI3K/AKT signaling pathway and mediate the invasion and liver metastasis of breast cancer through MMP1.