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Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections and plays a role in prostatic carcinogenesis and prostate cancer (PCa) progression. However, the mechanisms through which UPEC promotes PCa development and progression are unclear. Cytotoxic necrotizing factor 1 (CNF1) is one of the most important UPEC toxins and its role in PCa progression has never been studied. We found that UPEC-secreted CNF1 promoted the migration and invasion of PCa cells and PCa metastasis. In vitro studies showed that CNF1 promotes pro-migratory and pro-invasive activity through entering PCa cells and activating Cdc42, which subsequently induced PAK1 phosphorylation and up-regulation of MMP-9 expression. CNF1 also promoted pulmonary metastasis in a xenograft mouse model through these mechanisms. PAK1 phosphorylation correlated with advanced grades of PCa in human clinical PCa tissues. These results suggest that CNF1 derived from UPEC plays an important role in PCa progression through activating a Cdc42-PAK1 signal axis and up-regulating the expression of MMP-9. Therefore, surveillance for and treatment of cnf1-carrying UPEC strains may diminish PCa progression and thus have an important clinical therapeutic impact. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs), inducing acute pyelonephritis and may result in permanent renal scarring and failure. Alpha-hemolysin (HlyA), a key UPEC toxin, causes serious tissue damage; however, the mechanism through which HlyA induces kidney injury remains unclear. In the present study, granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by renal epithelial cells was upregulated by HlyA in vitro and in vivo, which induced M1 macrophage accumulation in kidney, and ADAM10 was found involved in HlyA-induced GM-CSF. Macrophage elimination or GM-CSF neutralization protected against acute kidney injury in mice, and increased GM-CSF was detected in urine of patients infected by hlyA-positive UPEC. In addition, HlyA was found to promote UPEC invasion into renal epithelial cells by interacting with Nectin-2 in vitro. However, HlyA did not affect bacterial titers during acute kidney infections, and HlyA-induced invasion did not contribute to GM-CSF upregulation in vitro, which indicate that HlyA-induced GM-CSF is independent of bacteria invasion. The role of GM-CSF in HlyA-mediated kidney injury may lead to novel strategies to treat acute pyelonephritis.

Anaemia is the most common complication of myeloma and is associated with worse clinical outcomes. Although marrow replacement with myeloma cells is widely considered a mechanistic rationale for anaemia, the exact process has not been fully understood. Our large cohort of 1363 myeloma patients had more than 50% of patients with moderate or severe anaemia at the time of diagnosis. Anaemia positively correlated with myeloma cell infiltration in the bone marrow (BM) and worse patient outcomes. The quantity and erythroid differentiation of HSPCs were affected by myeloma cell infiltration in the BM. The master regulators of erythropoiesis, GATA1 and KLF1, were obviously downregulated in myeloma HSPCs. However, the gene encoding the chemokine CCL3 showed significantly upregulated expression. Elevated CCL3 in the BM plasma of myeloma further inhibited the erythropoiesis of HSPCs via activation of CCL3/CCR1/p38 signalling and suppressed GATA1 expression. Treatment with a CCR1 antagonist effectively recovered GATA1 expression and rescued erythropoiesis in HSPCs. Myeloma cell infiltration causes elevated expression of CCL3 in BM, which suppresses the erythropoiesis of HSPCs and results in anaemia by downregulating the level of GATA1 in HSPCs. Thus, our study indicates that targeting CCL3 would be a potential strategy against anaemia and improve the survival of myeloma patients.

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