KIF23 regulation by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma

Abstract

AbstractBackground & AimsIn hepatocellular carcinoma, there is a lack of successful translation of experimental targets identified in mouse models to human patients. In this study, we used a comprehensive transcriptomic approach in mice to identify novel potential targets for therapeutic intervention in humans.MethodsWe analysed combined genome-wide miRNA and mRNA expression data in three pathogenically distinct mouse models of liver cancer. Effects of target genes on hepatoma cell fitness were evaluated by proliferation, survival and motility assays. TCGA and GEO databases, in combination with tissue microarrays (TMA), were used to validate the mouse targets and their impact on human HCC prognosis. Finally, the functional effects of the identified targets on tumorigenesis and tumor therapy were tested in hydrodynamic tail vein injection (HDTVi)-based preclinical HCC modelsin vivo.ResultsThe expression of miR-107 was found to be significantly reduced in mouse models of liver tumors of various etiologies and in cohorts of human HCC patients. Overexpression of miR-107 or inhibition of its novel target Kinesin family member 23 (Kif23) significantly reduced proliferation by interfering with cytokinesis, thereby controlling survival and motility of mouse and human hepatoma cells. In humans, KIF23 expression was found to be a prognostic marker in liver cancer, with high expression associated with poor prognosis. HDTVi of vectors carrying either pre-miR- 107 or anti-Kif23 shRNA inhibited the development of highly aggressive cMyc-NRas- induced liver cancers in mice.ConclusionsDisruption of the miR-107/Kif23 axis inhibited hepatoma cell proliferationin vitroand prevented oncogene-induced liver cancer developmentin vivo, offering a novel potential avenue for the treatment of HCC in humans.Impact and implicationsA comprehensive analysis integratingin silicoprediction, miRNA and mRNA data in three pathogenically distinct mouse models provided novel targets for the treatment of human HCC, bridging the translational gap between mouse data and human HCC. Our functional findings on the novel miR-107/Kif23 module provide important new insights into the control of mitosis in liver cancer cells. The findings that miR-107 overexpression or Kif23 inhibition had a dramatic functional effect on inhibiting the growth of liver cancer cellsin vitroandin vivosuggest that the miR-107/Kif23 axis may be a promising novel target and potential adjunct to sequential systemic therapy of HCC.Graphical abstractHighlightsmiR-107 is globally downregulated in mouse liver cancers of different etiologies and represents a potential biomarker in human HCC.Integration ofin-silico-prediction, miRNA and mRNA transcriptomics identified KIF23, a mitotic spindle-associated protein, as a specific target mediating the biological effects of miR-107.The miR-107/KIF23 module promotes replicative fitness of liver cancer cells through an essential function in cytokinesisMice receiving shRNA targeting Kif23 were completely protected from oncogene-induced liver cancer.