Lipopolysaccharide Promoted Stemness Of Castration-resistant Prostate Cancer Cells Through TLR4/MAPK/YAP Signaling

Background:The enhancement of stemness in prostate cancer cells is an important factor affecting the prognosis of prostate cancer patients.However,However,the reason why prostate cancer cells transform to stem cell phenotypes remains to be explored.Gram-negative bacteria are common in microbiota of the prostate cancer tissues,and the lipopolysaccharide(LPS)which is the key functional compound arise from the bacteria plays an important role in the development and progression of prostate cancer.Objective: Despite recent advances in the study of inflammation and microbiome in prostate cancer,the role of LPS on the stemness of prostate cancer cells and the potential mechanism is still unclarified.Therefore,this study focused on exploring the possible mechanism of LPS on the transformation of prostate cancer cells into stem cell phenotypes.Methods: PCR,WB and IF were used to detect YAP1’s expression level and related signaling pathways.Stemness was detected by Sphere formation assay,cell proliferation was analyzed by clone formation assay and EDU assay,and chemotherapy resistance was analyzed by Cell Count Kit 8.In vivo tumorigenicity experiments was performed in BALB/C nude mice.KI67 staining and TUNEL staining were used to analyze the prostate tumor tissues.Cut tag assay and co-immunofluorescence were used to verify the mechanism.Patients’ RNA-seq data were analyzed in the TCGA database for integration verification.Results: In this study,we found LPS promoted stemness of castration-resistant prostate cancer(CRPC)cells and increased stemness of CRPC cells caused by LPS contributed to the resistance to chemotherapy.Mechanically,we found that LPS/TLR4/p38 MAPK signaling enhanced YAP1 phosphorylation state and nuclear translocation via suppressing the activation of Hippo pathway.YAP/TAZ-TEADs transcription complex could directly regulate the transcription of Sox2 and finally lead to upregulation of stemness of prostate cancer cells.Conclusions: The results of our study indicated that LPS promoted stemness of CRPC cells via TLR4-p38 MAPK-YAP signal pathway which provide new insights for understanding the potential mechanism of stemness maintaining of CRPC cells.