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

Xia Wang, Jin Wang, Yu-Man Tsui, Chaoran Shi, Ying Wang, Xin Zhang, Qian Yan, Miao Chen, Chen Jiang, Yun-Fei Yuan, Chun-Ming Wong, Ming Liu, Zeng-yu Feng, Honglin Chen, Irene Oi Lin Ng, Lingxi Jiang () and Xin-Yuan Guan ()
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Xia Wang: The University of Hong Kong
Jin Wang: The University of Hong Kong
Yu-Man Tsui: The University of Hong Kong
Chaoran Shi: The University of Hong Kong
Ying Wang: The University of Hong Kong
Xin Zhang: The University of Hong Kong
Qian Yan: The University of Hong Kong
Miao Chen: The University of Hong Kong
Chen Jiang: The University of Hong Kong
Yun-Fei Yuan: Sun Yat-Sen University Cancer Center
Chun-Ming Wong: The University of Hong Kong
Ming Liu: The University of Hong Kong
Zeng-yu Feng: Shanghai JiaoTong University School of Medicine
Honglin Chen: The University of Hong Kong
Irene Oi Lin Ng: The University of Hong Kong
Lingxi Jiang: The University of Hong Kong
Xin-Yuan Guan: The University of Hong Kong

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21828-7

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