NAT10 affects the progression of intrahepatic cholangiocarcinoma and M2-type polarization of macrophages by regulating CCL2

Abstract Intrahepatic cholangiocarcinoma (ICC) is a highly lethal hepatobiliary tumor and its incidence is on the rise. As a cancer of unknown primary causes, the pathogenesis and related biomarkers of ICC still needs to be investigated. N-acetyltransferase 10 (NAT10) is essential for cellular mRNA stability and tumor cell progression; however, the detailed mechanism underlying its role in ICC is unknown. Here, we examined the role of NAT10 in ICC and deeply investigated its effect on macrophage polarization. Tissue microarray (TMA) analysis shown that high expression of NAT10 was positively associated with poor clinicopathological manifestations of CCA. Silencing of NAT10 inhibited the proliferation of ICC cells in vitro and tumor growth in vivo, whereas NAT10 overexpression promoted ICC progression. Mechanistically, NAT10 binds to the C-C motif chemokine ligand 2 (CCL2) mRNA and elevates its protein levels, thereby promoting the proliferation of ICC cells and M2 polarization of macrophages. Molecular docking screening and the surface plasmon resonance (SPR) identified a natural product, berberine (BBR), which targeted CCL2 and thereby inhibited ICC progression and reduced M2 polarization of macrophages. In summary, NAT10 promotes ICC progression and M2 polarization of macrophages by increasing CCL2. BBR inhibits ICC progression by targeting CCL2 and is an attractive novel compound for targeted therapy.