ADAMTSL5 is an epigenetically activated oncogene conferring tumorigenic properties in hepatocellular carcinoma

The remarkable molecular heterogeneity in hepatocellular carcinoma (HCC) continues to challenge development of effective treatments and biomarkers. Here we report that the gene encoding a secreted glycoprotein, ADAMTSL5, is overexpressed and displays hypermethylated CpG islands in its gene body region in a clinically relevant mouse genetic model of HCC as well as in a significant proportion of human HCC patients. Immunohistological analysis of human HCCs revealed strong ADAMTSL5 immunostaining in tumour cells and histiocytes, in contrast to normal liver. Functional targeting of ADAMTSL5 in oncogenesis using shRNA interfered with tumorigenic properties of HCC cells both in vitro and in vivo. Furthermore, ADAMTSL5 overexpression conferred tumorigenic capability to genetically sensitized, non-transformed hepatocytes in nude mice. Mechanistically, ADAMTSL5 abrogation led to reduction of several oncogenic inputs, including the receptor tyrosine kinases MET, EGFR, PDGFRβ, IGF1Rβ, and FGFR4, suggesting it as a master regulator of HCC tumorigenicity when overexpressed.