RALYL increases hepatocellular carcinoma stemness by sustaining the mRNA stability of TGF-β2

• Published in: Nature communications Vol. 12; no. 1; pp. 1518 - 14
• Main Authors: Wang, Xia, Wang, Jin, Tsui, Yu-Man, Shi, Chaoran, Wang, Ying, Zhang, Xin, Yan, Qian, Chen, Miao, Jiang, Chen, Yuan, Yun-Fei, Wong, Chun-Ming, Liu, Ming, Feng, Zeng-yu, Chen, Honglin, Ng, Irene Oi Lin, Jiang, Lingxi, Guan, Xin-Yuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/106; 13/109; 38/77; 38/90; 38/91; 631/67; 631/67/1504/1610; 82/80; AKT protein; Animals; Cancer; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell self-renewal; Chemoresistance; Embryo cells; Embryonic Stem Cells; Female; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Hepatocytes; Heterogeneous-Nuclear Ribonucleoprotein Group C - genetics; Heterogeneous-Nuclear Ribonucleoprotein Group C - metabolism; Humanities and Social Sciences; Humans; Liver; Liver - metabolism; Liver - pathology; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Metastases; Metastasis; Mice; Middle Aged; mRNA stability; multidisciplinary; N6-methyladenosine; Neoplastic Stem Cells - metabolism; Phenotypes; Phosphatidylinositol 3-Kinases - metabolism; Progenitor cells; RNA Stability - physiology; RNA-binding protein; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction - genetics; Stability; Stat3 protein; STAT3 Transcription Factor - metabolism; Stem cells; Transforming Growth Factor beta2 - metabolism; Tumorigenicity; Up-Regulation
• DOI: 10.1038/s41467-021-21828-7
• ISSN: 2041-1723

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 (m 6 A) 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. RALYL is a liver progenitor cell-specific gene but its role in hepatocellular carcinoma (HCC) remains unknown. Here, the authors demonstrate that RALYL regulates HCC stemness through upregulation of TGF-β2 mRNA stability by decreasing N6-methyladenosine modification.