Open AccessSRY and OCT4 Are Required for the Acquisition of Cancer Stem Cell‐Like Properties and Are Potential Differentiation Therapy Targets
Author(s) -
Murakami Shigekazu,
Ninomiya Wataru,
Sakamoto Erina,
Shibata Tatsuhiro,
Akiyama Hirotada,
Tashiro Fumio
Publication year - 2015
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2059
Subject(s) - testis determining factor , biology , hccs , gene knockdown , cancer stem cell , cancer research , stem cell , microbiology and biotechnology , hepatocellular carcinoma , genetics , cell culture , gene , y chromosome
The acquisition of stemness is a hallmark of aggressive human hepatocellular carcinoma (hHCC). The stem cell marker OCT4 is frequently expressed in HCCs, and its expression correlates with those of putative cancer stem cell (CSC) markers and CSC properties. Here, we describe a novel mechanism of CSC maintenance by SRY through OCT4. We previously reported that Sry is involved in tumor malignancy in rodent HCCs. However, the oncogenic function of SRY in hHCCs is poorly understood. Ectopic expression of SRY increased multiple stem cell factors, including OCT4 and CD13 . The OCT4 promoter contained SRY‐binding sites that were directly activated by SRY. In HCC‐derived cells, SRY knockdown decreased OCT4 expression and cancer stem‐like phenotypes such as self‐renewal, chemoresistance, and tumorigenicity. Conversely, OCT4 and SRY overexpression promoted cancer stem‐like phenotypes. OCT4 knockdown in SRY clones downregulated the self‐renewal capacity and chemoresistance. These data suggest that SRY is involved in the maintenance of cancer stem‐like characteristics through OCT4. Moreover, CSCs of HCC‐derived cells differentiated into Tuj1‐positive neuron‐like cells by retinoic acid. Noteworthily, SRY was highly expressed in some hHCC patients. Taken together, our findings imply a novel therapeutic strategy against CSCs of hHCCs. S tem C ells 2015;33:2652–2663