Gut Dysbiosis Promotes Prostate Cancer Progression And Docetaxel Resistance

Background and objectiveProstate cancer(PCa)is the most common malignant tumor of male genitourinary system.The gut microbiota is reportedly involved in the progression and chemoresistance of various human malignancies.However,the underlying mechanisms behind how it exerts some effect on PCa,as an extra-intestinal tumor,in a contact-independent way remain elusive and deserve exploration.Antibiotics exposure,one of the various factors affecting the gut microbiota community and capable of causing gut dysbiosis,is associated with multiple disorders.This study aims to preliminarily clarify the link between gut dysbiosis and PCa.MethodsA gut dysbiosis murine model was created by feeding C57BL/6 male mice with broad-spectrum antibiotics,and the prostate cancer cell RM-1 was inoculated to observe the effect of gut dysbiosis on the growth of subcutaneous and orthotopic transplanted tumor.16S rRNA sequencing analysis was applied to identify the composition of the gut microbiota both in mice and human patients.ELISA,Western Blot,RT-qPCR,immunofluorescence,and immunohistochemistry staining were performed to reveal the mechanisms.Biological function was assessed by cell viability,clone formation,Edu and TUNEL assays,and animal models.Correlation analysis was made between the sequencing results of gut microbiota in clinical patients and a variety of clinical parameters to preliminarily explore the clinical significance and application value of intestinal differential species.ResultsFirst,we discovered that perturbing the gut microbiota by consuming broad-spectrum antibiotics in water accelerated the growth of subcutaneous and orthotopic tumors in mice.Fecal microbiota transplantation could transmit the effect of antibiotics exposure on tumor growth.Then,16S rRNA sequencing for mouse feces indicated that the relative abundance of Proteobacteria was significantly higher after antibiotics exposure.Meanwhile,intratumoral lipopolysaccharide(LPS)profoundly increased under the elevation of gut permeability.Both in vivo and in vitro experiments revealed that NF-κB-IL6-STAT3 axis activated by intratumoral LPS facilitated PCa proliferation and docetaxel chemoresistance.Finally,16S rRNA sequencing of patients’ fecal samples revealed that the relative abundance of intestinal Proteobacteria was increased in patients with metastatic PCa,and was positively correlated with plasma IL6 level,regional lymph node metastasis status,and distant metastasis status.The receiver operating characteristic(ROC)curves showed that the relative abundance of Proteobacteria had better performance than plasma prostate specific antigen level in predicting the probability of distant metastasis in PCa(area under the ROC curve,0.860;p<0.001).ConclusionCollectively,this research demonstrated that gut dysbiosis,characterized by the enrichment of Proteobacteria due to antibiotics exposure,resulted in the elevation of gut permeability and intratumoral LPS,promoting the development of PCa via NF-κB-IL6-STAT3 axis in mice.Considering findings from human patients,Proteobacteria might act as an intestinal biomarker for progressive PCa.