Environmental exposure to microcystin-LR increases the risks of urinary bladder proliferation and carcinogenesis: Evidence from case control, animal, and in vitro studies

Abstract

To date, no reported studies have explored the impacts of microcystin-LR (MC-LR) on bladder tissues, and even the occurrence of bladder cancer. The current study explores the role of MC-LR in the development of bladder cancer through human observation and experimental research. In the population study, the odds ratio of bladder cancer for MC-LR was 6.073 (95 % CI, 2.117–17.422) after adjusting interference confounders. MC-LR is mainly located in the nucleus of epithelial cells in bladder cancer tissues instead of normal tissues. A positive association was observed between MC-LR and advanced tumor stage in serum and tissues. The animal study confirmed that prolonged MC-LR treatment promoted the bladder cancer phenotype accompanied by urinary bladder proliferation. In vitro, we indicated that MC-LR activated the PI3K/AKT/GSK3β/Cyclin D1 and JAK2/STAT3/Bcl2 signaling pathways to induce the growth of SV-HUC-1 cells. Moreover, MC-LR promoted the angiogenesis of SV-HUC-1 cells through PI3K/AKT/mTOR/HIF-1α/VEGF pathway. Our study provided the first evidence that prolonged MC-LR treatment increases the incidence of bladder cancer from human investigations, mice models, and in vitro studies, implying the profound importance of the investigation of MC-LR for public health.