FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells.

ABSTRACT

Cancer associated fibroblast (CAF) is a well-known microenvironment contributor for the development of hepatocellular carcinoma (HCC), while forkhead box (FOX) proteins are also critical to exacerbate HCC malignancy. However, whether FOX proteins are involved in the crosstalk between CAFs and HCC cells remains unclear. In the present study, we reveal that CAFs induce forkhead box Q1 (FOXQ1) expression, and N-myc downstream-regulated gene 1 (NDRG1) is therefore trans-activated to enhance HCC initiation. Intriguingly, pSTAT6/C-C motif chemokine ligand 26 (CCL26) signaling is induced by FOXQ1/NDRG1 axis, thus recruiting hepatic stellate cells (HSCs), the main cellular source of CAFs, to the tumor microenvironment. Thereby, tumor initiating properties are enhanced at least partly through a positive feedback loop between CAFs and HCC cells. Importantly, leflunomide, a pSTAT6 inhibitor that has been approved for the treatment of rheumatoid arthritis, significantly blocks the loop and HCC progression. High expression of CAF marker, ACTA2, and induced FOXQ1/NDRG1 axis in HCC tissues predict unfavorable prognosis. Collectively, our findings uncover a positive feedback loop between CAFs and FOXQ1/NDRG1 axis in neoplastic cells to drive HCC initiation, thus providing new potential therapeutic targets for HCC.