Chronic inflammation is a key driver for colitis-associated colorectal cancer (CAC). It has been reported that inflammatory cytokines, such as IL-1β, could promote CAC. Zinc finger protein 70 (ZNF70) is involved in multiple biological processes. Here, we identified a previously unknown role for ZNF70 regulates macrophages IL-1β secretion to promote HCT116 proliferation in CAC, and investigated its underlying mechanism. We showed ZNF70 is much higher expressed in CAC tumor tissues compared with adjacent normal tissues in clinical CAC samples. Further experiments showed ZNF70 promoted macrophages IL-1β secretion and HCT116 proliferation. In LPS/ATP-stimulated THP-1 cells, we found ZNF70 activated NLRP3 inflamm... More
Chronic inflammation is a key driver for colitis-associated colorectal cancer (CAC). It has been reported that inflammatory cytokines, such as IL-1β, could promote CAC. Zinc finger protein 70 (ZNF70) is involved in multiple biological processes. Here, we identified a previously unknown role for ZNF70 regulates macrophages IL-1β secretion to promote HCT116 proliferation in CAC, and investigated its underlying mechanism. We showed ZNF70 is much higher expressed in CAC tumor tissues compared with adjacent normal tissues in clinical CAC samples. Further experiments showed ZNF70 promoted macrophages IL-1β secretion and HCT116 proliferation. In LPS/ATP-stimulated THP-1 cells, we found ZNF70 activated NLRP3 inflammasome, resulting in robust IL-1β secretion. Interestingly, we discovered the ZnF domain of ZNF70 could interact with NLRP3 and decrease the K48-linked ubiquitination of NLRP3. Moreover, ZNF70 could activate STAT3, thereby promoting IL-1β synthesis. Noteworthy, ZNF70 enhanced proliferation by upregulating STAT3 activation in HCT116 cells cultured in the conditioned medium of THP-1 macrophages treated with LPS/ATP. Finally, the vivo observations were confirmed using AAV-mediated ZNF70 knockdown, which improved colitis-associated colorectal cancer in the AOM/DSS model. The correlation between ZNF70 expression and overall survival/IL-1β expression in colorectal cancer was verified by TCGA database. Taken together, ZNF70 regulates macrophages IL-1β secretion to promote the HCT116 cells proliferation via activation of NLRP3 inflammasome and STAT3 pathway, suggesting that ZNF70 may be a promising preventive target for treating in CAC.
