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Background <p>Hepatocellular carcinoma (HCC) ranks among the primary causes of cancer-related mortality, underscoring the urgent need for novel therapeutic strategies. The Hedgehog (Hh) signaling pathway, particularly the stabilization of GLI2, plays a pivotal role in cancer progression. This study aims to elucidate the functional role of heterogeneous nuclear ribonucleoprotein A3 (hnRNPA3) in HCC and its mechanistic association with GLI2 stabilization and Hh pathway activation.</p> Methods <p>hnRNPA3 expression levels were systematically evaluated in HCC tissues using Western blot analysis, immunohistochemistry (IHC), and survival analysis. Functional characterization was performed through in vitro assays, including CCK8 proliferation assays, colony formation assays, and xenograft models in vivo. Mechanistic investigations employed coimmunoprecipitation (Co-IP), mass spectrometry (LC-MS/MS), ubiquitination assays, and dual-luciferase reporter systems.</p> Results <p>Elevated hnRNPA3 expression was consistently observed in HCC tissues and significantly correlated with poor prognosis. Overexpression of hnRNPA3 promoted HCC cell proliferation in vitro and tumor growth in vivo, whereas its knockdown exerted suppressive effects. Mechanistically, hnRNPA3 directly interacted with GLI2, inhibiting FBXW11-mediated ubiquitination and subsequent proteasomal degradation, thereby stabilizing GLI2 and activating Hh signaling pathways. Pharmacological inhibition of GLI1/2 via GANT61 effectively reversed hnRNPA3-induced proliferation.</p> Conclusions <p>hnRNPA3 stabilizes GLI2 by disrupting its interaction with FBXW11, thereby enhancing Hh pathway activity and contributing to HCC progression. These findings position hnRNPA3 as a potential prognostic biomarker and therapeutic target for HCC, warranting further investigation.</p> Graphical abstract <p></p>

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hnRNPA3 promotes the proliferation of hepatocellular carcinoma cells by stabilizing GLI2 proteins and activating Hedgehog pathway

  • 期刊论文

  • 发表日期：

    2025年11月5日

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  • Xuesi Tian,
  • Jiayu Luo,
  • Can Chen,
  • Limin Chen,
  • Zhenyu Zhai,
  • Linlin Xu,
  • Minzhang Cheng,
  • Shiwen Luo,
  • Hailong Wang

摘要

Background

Hepatocellular carcinoma (HCC) ranks among the primary causes of cancer-related mortality, underscoring the urgent need for novel therapeutic strategies. The Hedgehog (Hh) signaling pathway, particularly the stabilization of GLI2, plays a pivotal role in cancer progression. This study aims to elucidate the functional role of heterogeneous nuclear ribonucleoprotein A3 (hnRNPA3) in HCC and its mechanistic association with GLI2 stabilization and Hh pathway activation.

Methods

hnRNPA3 expression levels were systematically evaluated in HCC tissues using Western blot analysis, immunohistochemistry (IHC), and survival analysis. Functional characterization was performed through in vitro assays, including CCK8 proliferation assays, colony formation assays, and xenograft models in vivo. Mechanistic investigations employed coimmunoprecipitation (Co-IP), mass spectrometry (LC-MS/MS), ubiquitination assays, and dual-luciferase reporter systems.

Results

Elevated hnRNPA3 expression was consistently observed in HCC tissues and significantly correlated with poor prognosis. Overexpression of hnRNPA3 promoted HCC cell proliferation in vitro and tumor growth in vivo, whereas its knockdown exerted suppressive effects. Mechanistically, hnRNPA3 directly interacted with GLI2, inhibiting FBXW11-mediated ubiquitination and subsequent proteasomal degradation, thereby stabilizing GLI2 and activating Hh signaling pathways. Pharmacological inhibition of GLI1/2 via GANT61 effectively reversed hnRNPA3-induced proliferation.

Conclusions

hnRNPA3 stabilizes GLI2 by disrupting its interaction with FBXW11, thereby enhancing Hh pathway activity and contributing to HCC progression. These findings position hnRNPA3 as a potential prognostic biomarker and therapeutic target for HCC, warranting further investigation.

Graphical abstract