Oct4 is a reliable marker of liver tumor propagating cells in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the 6th most common cancer worldwide and the 2nd most common cause of cancer related mortality. The poor prognosis is largely due to the difficulty in early diagnoses and eradication of stem-like cells within HCC, which are termed liver tumor propagating cells (LTPCs). These LTPCs are involved in all stages of tumorigenesis including tumor initiation, progression, and treatment failure. The greatest challenge in understanding these LTPCs is finding effective ways in isolating and characterizing these cells with current methods showing large inter-tumor variability in isolating these cells. Oct4 is a stem cell gene associated with LTPCs and has been shown to be involved in regulating a range of functions in HCC cells associated with LTPC features. In this study we determined the efficacy and reliability in utilizing Oct4 to isolate and characterize LTPCs. We have shown that Oct4 is ubiquitously expressed in all HCC tumors tested whereas other traditional LTPC markers had high intratumor variability in their expression. We then utilized a human Oct4 promoter driving an enhanced green fluorescent protein (EGFP) reporter which showed that Oct4+ cells had all the classic features of LTPCs including increased sphere formation in vitro, tumor forming potential in immunocompromised mice, expression of stemness associated genes, and resistance to Sorafenib which is the major drug used to treat advanced HCC. Based on our findings we have identified Oct4 as a reliable marker of LTPCs and discovered a novel way to isolate and characterize LTPCs