Collectin-11 promotes cancer cell proliferation and tumor growth.

Collectin-11 (CL-11) is a recently described soluble C-type lectin that has distinct roles in embryonic development, host defence, autoimmunity, and fibrosis. Here we report that CL-11 also plays an important role in cancer cell proliferation and tumor growth. Melanoma growth was found to be suppressed in Colec11-/- mice in a s.c. B16 melanoma model. Cellular and molecular analyses revealed that CL-11 is essential for melanoma cell proliferation, angiogenesis, establishment of more immunosuppressive tumor microenvironment, and the reprogramming of macrophages to M2 phenotype within melanomas. In vitro analysis revealed that CL-11 can activate tyrosine kinase receptors (EGFR, HER3) and ERK, JNK, and AKT signaling pathways and has a direct stimulatory effect on murine melanoma cell proliferation. Furthermore, blockade of CL-11 (treatment with L-fucose) inhibited melanoma growth in mice. Analysis of open data sets revealed that COLEC11 gene expression is upregulated in human melanomas and that high COLEC11 expression has a trend toward poor survival. CL-11 also had direct stimulatory effects on human tumor cell proliferation in melanoma and several other types of cancer cells in vitro. Overall, our findings provide the first evidence to our knowledge that CL-11 is a key tumor growth-promoting protein and a promising therapeutic target in tumor growth.

Epithelial C5aR1 Signaling Enhances Uropathogenic Escherichia coli Adhesion to Human Renal Tubular Epithelial Cells.

Recent work in a murine model of ascending urinary tract infection has suggested that C5a/C5aR1 interactions play a pathogenic role in the development of renal infection through enhancement of bacterial adhesion/colonization to renal tubular epithelial cells (RTECs). In the present study, we extended these observations to human. We show that renal tubular epithelial C5aR1 signaling is involved in promoting uropathogenic Escherichia coli (UPEC) adhesion/invasion of host cells. Stimulation of primary cultures of RTEC with C5a resulted in significant increases in UPEC adhesion/invasion of the RTEC. This was associated with enhanced expression of terminal α-mannosyl residues (Man) (a ligand for type 1 fimbriae of E. coli) in the RTEC following C5a stimulation. Mechanism studies revealed that C5aR1-mediated activation of ERK1/2/NF-κB and upregulation of proinflammatory cytokine production (i.e., TNF-α) is at least partly responsible for the upregulation of Man expression and bacterial adhesion. Clinical sample studies showed that C5aR1 and Man were clearly detected in the renal tubular epithelium of normal human kidney biopsies, and UPEC bound to the epithelium in a d-mannose-dependent manner. Additionally, C5a levels were significantly increased in urine of urinary tract infection patients compared with healthy controls. Our data therefore demonstrate that, in agreement with observations in mice, human renal tubular epithelial C5aR1 signaling can upregulate Man expression in RTEC, which enhances UPEC adhesion to and invasion of RTEC. It also suggests the in vivo relevance of upregulation of Man expression in renal tubular epithelium by C5a/C5aR1 interactions and its potential impact on renal infection.