Abstract
Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells. In the present study, human embryonic stem cells are induced to differentiate into hepatocytes along hepatic lineages to mimic liver development in vitro. A liver progenitor specific gene, RALY RNA binding protein like (RALYL), is identified. RALYL expression is associated with poor prognosis, poor differentiation, and metastasis in clinical HCC patients. Functional studies reveal that RALYL could promote HCC tumorigenicity, self-renewal, chemoresistance, and metastasis. Moreover, molecular mechanism studies show that RALYL could upregulate TGF-β2 mRNA stability by decreasing N6-methyladenosine (m6A) modification. TGF-β signaling and the subsequent PI3K/AKT and STAT3 pathways, upregulated by RALYL, contribute to the enhancement of HCC stemness. Collectively, RALYL is a liver progenitor specific gene and regulates HCC stemness by sustaining TGF-β2 mRNA stability. These findings may inspire precise therapeutic strategies for HCC.
Highlights
Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells
The specific markers were highly expressed in their corresponding stages. quantitative real-time PCR (qRT-PCR) demonstrated that these specific markers, including embryonic stem (ES) markers (OCT4 and SOX2), definitive endoderm (DE) markers (SOX17 and FOXA2), liver progenitor (LP) markers (CK19 and AFP), and hepatocyte markers (ALB and CYP3A4), were highly expressed in their corresponding stages (Supplementary Fig. 1a)
Emerging evidence suggests that cancer stem cells (CSCs) and tissue progenitor cells shared many common properties, which are widely applied by histopathologists to define the differentiation level of certain types of tumors[34]
Summary
Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells. RALYL is a liver progenitor specific gene and regulates HCC stemness by sustaining TGF-β2 mRNA stability. These findings may inspire precise therapeutic strategies for HCC. Evidence shows that CSCs are responsible for the initiation and development of tumors and are endowed with tissue progenitor cell features, such as the capabilities to maintain self-renewal and differentiation[1,2,3]. Further molecular study showed that liver CSCs and liver progenitor cells share similar gene expression patterns such as AFP, CK19, EpCAM, CD133, and CD9013. Network analysis have revealed several novel specific biomarkers and potential oncogenic drivers, of which, a liver progenitor cell-specific gene, RALY RNA binding proteinlike (RALYL) was investigated in this study. The roles of RALYL in liver CSCs may provide potential oncogenic driver, ideal for HCC therapeutic targets
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