Urinary sp. Promotes Non-Muscle Invasive Bladder Cancer (NMIBC) Development through the ECM1/MMP9 Pathway.

BACKGROUND

Increasing evidence points to the urinary microbiota as a possible key susceptibility factor for early-stage bladder cancer (BCa) progression. However, the interpretation of its underlying mechanism is often insufficient, given that various environmental conditions have affected the composition of urinary microbiota. Herein, we sought to rule out confounding factors and clarify how urinary sp. promoted non-muscle invasive bladder cancer (NMIBC) development.

METHODS

Differentially abundant urinary microbiota of 51 NMIBC patients and 47 healthy controls (as Cohort 1) were first determined by metagenomics analysis. Then, we modeled the coculture of NMIBC organoids with candidate urinary sp. in anaerobic conditions and explored differentially expressed genes of these NMIBC tissues by RNA-Seq. Furthermore, we dissected the mechanisms involved into sp. by inducing extracellular matrix protein 1 (ECM1) and matrix metalloproteinase 9 (MMP9) upregulation. Finally, we used multivariate Cox modeling to investigate the clinical relevance of urinary sp. 16S ribosomal RNA (16SrRNA) levels to the prognosis of 406 NMIBC patients (as Cohort 2).

RESULTS

sp. infection accelerated the proliferation of NMIBC organoids ( < 0.01); ECM1 and MMP9 were the most upregulated genes induced by the increased colony forming units (CFU) gradient of sp. infection via phosphorylating ERK1/2 in NMIBC organoids of Cohort 1. Excluding the favorable impact of potential contributing factors, the ROC curve of Cohort 2 manifested its 3-year AUC value as 0.79 and the cut-off point of sp. 16SrRNA as 10.3 (delta CT value).

CONCLUSION

Our evidence suggests that urinary sp. promoted NMIBC progression through the ECM1/MMP9 pathway, which may serve as the promising noninvasive diagnostic biomarker for NMIBC.