Although OPN serves as a marker for biliary epithelial cells (BECs) and hepatic progenitor cells (HPCs), and a small number of OPN-positive cells contribute to liver regeneration after certain chronic injuries [51,52], lineage-tracing studies in multiple toxin-induced HCC models indicate that OPN-labeled BECs/HPCs do not directly give rise to tumors, suggesting that hepatocytes are the primary cell origin of HCC under these conditions  [53,54]. This evidence concerns the gene SPP1 and hepatocellular carcinoma.