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

Author

Listed:
  • Xia Wang

    (The University of Hong Kong
    The University of Hong Kong
    The University of Hong Kong)

  • Jin Wang

    (The University of Hong Kong)

  • Yu-Man Tsui

    (The University of Hong Kong
    The University of Hong Kong)

  • Chaoran Shi

    (The University of Hong Kong
    The University of Hong Kong)

  • Ying Wang

    (The University of Hong Kong
    The University of Hong Kong
    Sun Yat-Sen University Cancer Center)

  • Xin Zhang

    (The University of Hong Kong
    The University of Hong Kong)

  • Qian Yan

    (The University of Hong Kong
    The University of Hong Kong)

  • Miao Chen

    (The University of Hong Kong
    The University of Hong Kong)

  • Chen Jiang

    (The University of Hong Kong
    Sun Yat-Sen University Cancer Center
    Sun Yat-Sen University Cancer Center)

  • Yun-Fei Yuan

    (Sun Yat-Sen University Cancer Center)

  • Chun-Ming Wong

    (The University of Hong Kong
    The University of Hong Kong)

  • Ming Liu

    (The University of Hong Kong
    The University of Hong Kong
    Guangzhou Medical University)

  • 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
    The University of Hong Kong)

  • Lingxi Jiang

    (The University of Hong Kong
    Shanghai JiaoTong University School of Medicine)

  • Xin-Yuan Guan

    (The University of Hong Kong
    The University of Hong Kong)

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.

Suggested Citation

  • 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 &, 2021. "RALYL increases hepatocellular carcinoma stemness by sustaining the mRNA stability of TGF-β2," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21828-7
    DOI: 10.1038/s41467-021-21828-7
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    Cited by:

    1. Ki-Fong Man & Lei Zhou & Huajian Yu & Ka-Hei Lam & Wei Cheng & Jun Yu & Terence K. Lee & Jing-Ping Yun & Xin-Yuan Guan & Ming Liu & Stephanie Ma, 2023. "SPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Maarten H. Geurts & Shashank Gandhi & Matteo G. Boretto & Ninouk Akkerman & Lucca L. M. Derks & Gijs Son & Martina Celotti & Sarina Harshuk-Shabso & Flavia Peci & Harry Begthel & Delilah Hendriks & Pa, 2023. "One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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