e16005 Background: Metastasis is the main cause of cancer-related death governed by both cancer cell-intrinsic properties and extrinsic immune contexture. Our previous reports have suggested critical roles of KIAA1199 in tumor invasion and metastasis in colorectal cancer (CRC). In the present study, we explored the potential effects of KIAA1199 on pre-metastatic niche formation. Methods: The CIBERSORT algorithm analysis for 241 patients with colorectal cancer from the Cancer Genome Atlas was performed to investigate the relationship between KIAA1199 expression and neutrophil accumulation. Neutrophils and T cells were isolated, stimulated and/or cultured for in vitro function assays. Proteins were knocked down in MC38 and HCT116 colorectal cancer cell lines, which were analyzed by immunoblotting and chemotaxis assays. Results: We demonstrate that patients with high KIAA1199 showed an increased level of liver-infıltrating neutrophils, which is further validated using flow cytometry analyses in mouse metastasis model. The increased influx of neutrophils is associated with KIAA1199-driven CRC liver metastasis. Neutrophils isolated from pre-metastatic niche decreased CD8+ T cells infiltration and IFN-r+ CD8+ T cells proportion in vivo. Moreover, they showed a N2-like phenotype and expressed higher level immunosuppressive molecules when exposed to the supernatant of normal CRC cell compared to KIAA1199-knock down cell. In CRC cells, we also found a positive correlation between expression of KIAA1199 and genes that ELR+ chemotaxis of neutrophil (CXCL1/CXCL3/CXCL5), which recruited neutrophils to CRC tumor via CXCR2. Importantly, LY2109761, a TGF-β receptor inhibitor, is sufficient to reduce the mRNA levels of these genes. Furthermore, there is a positive correlation between expression of KIAA1199 and expression of Transforming Growth Factor beta pathway genes (TGFBR1, TGFBR2, and pSMAD3), and further co-immunoprecipitation analysis suggests that KIAA1199 may activate the TGF-β signaling pathway via interacting with the TGFBR1 or TGFBR2. Conclusions: Our data indicate that the upregulation of KIAA1199 may increase the expression of cytokines mediated by TGF-β signaling, which can recruit metastasis-supporting neutrophils to promote colorectal cancer liver metastasis. Blockade of the TGF-β signaling could be a novel therapeutic approach against KIAA1199-high expression CRC.
The prognostic role of KRAS and BRAF in patients undergoing surgical resection of colorectal cancer liver metastasis: a systematic review and meta-analysis
