Interleukin-17 mediates liver progenitor cell transformation into cancer stem cells through downregulation of miR-122

Objective: Cancer stem cells (CSCs) have been the focus ofseveral studies because oftheir involvement in cancer initiationand progression. CSCs were identified in 28% to 50% ofhepatocellular carcinomas (HCCs). The origin of CSCs is stillunclear, but it has been recently suggested that CSCs couldoriginate from the transformation of liver progenitor cells (LPCs)during chronic liver inflammation. We previously reporteda correlation between increased expansion of LPCs and thenumber of interleukin (IL)-17-producing cells. In this study,we hypothesized that chronic IL-17 exposure may lead to LPCtransformation into CSCs. Methods: Preneoplastic liver samples from 33 patients wereimmunostained with specific antibodies to identify LPCs (anti-CK19), CSCs (anti-CD133), and IL-17-producing cells (anti-IL-17).IL-17 tumorigenic effects were assessed in vivo, inNOD/SCIDmice that were subcutaneously engrafted with a murine LPCline, “Bipotential Murine Oval Liver (BMOL) transfected withluciferase and IL-17 genes or empty vector. Tumor growth wasfollowed over 12 weeks by bioluminescence imaging (IVIS Camerasystem). MicroRNA-regulated expression effect on IL-17-treatedBMOL cells over 40 days was determined by next-generationsequencing. Acquired self-renewal ability of transformed BMOLcells was assessed by spheroid formation capacity. Results: Semi-quantitative analysis of CK19+, CD133+, andIL-17+ cells in cirrhotic livers showed a positive correlationbetween the number of infiltrated IL-17+ cells and LPC andCSC accumulation. In vivo, when mice were engrafted withBMOL cells that constitutively producing IL-17, enhancedcell expansion was observed, in contrast to the conditionwhere BMOL cells with empty vector control were engrafted.Immunohistological and mRNA analyses of the tumors thatdeveloped at 12 weeks showed a significant increase in cancercell makers including CD133, α-fetoprotein, and glypican-3in the presence of IL-17. MiRNome analysis of BMOL treatedwith IL-17 revealed a 90% decrease in miR-122 expressionand this was accompanied by a higher self-renewal capacity.However, over expression of a miR-122 mimic in BMOL cellsabolished the IL-17-mediated self-renewal capacity. Conclusions: In preneoplastic liver samples, the correlationbetween IL-17+ cells and increased expression of CD133strongly suggests that IL-17 leads to LPC transformation intoCSCs. This was supported by aggressive tumor developmentin mice engrafted with LPCs in an IL-17-enrichedmicroenvironment. IL-17 mediates LPC transformationthrough miR-122 downregulation. Therefore, strategies aimingto neutralize IL-17 may contribute to CSC niche eradicationand could prevent HCC initiation. DOI: 10.20892/j.issn.2095-3941.2018.S124