Investigation into the acquisition mechanism of malignant phenotypes in aflatoxin B1-induced rat hepatocellular carcinoma K2 cells

The acquisition of stemness, which epigenetically induced and maintained by Yamanaka factors, Oct4, Sox2, Klf4, and c-Myc, is a hallmark of malignant hepatocellular carcinoma (HCC). We found that deregulated expression of Sry (sex-determing region Y) is involved in the acquisition of tumor malignancy of aflatoxin B1 (AFB1)-induced male rodent (r) HCC K2 cells, in which 89% of the population is cancer stem cells (CSCs) due to the robust potentiation of Sry/SGF29/c-Myc pathway. In human (h) HCCs, overexpressed Sry activates directly the CSC marker Oct4 expression, while its knockdown decreases Oct4 expression and CSC natures including selfrenewal, tumorigenicity and chemoresistance. Thus, these facts indicate that Sry takes part in the induction and maintenance of CSCs in HCCs. Moreover, CSCs from hHCCs could differentiate into Tuj1-positive and Ki67-negative neurons having long neurites in the presence of retinoic acid (RA). Taken together with the fact that deregulated expression of Sry mRNA can be detected in three out of the eighteen male patients with HCC tested, differentiation-inducing therapy targeting HCCs-derived CSCs, which play a central role in tumor redevelopment, is fully promised for rooting out of cancer.