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Background <p>Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a major global health burden due to its aggressive metastatic behavior and poor prognosis. Clarification of the molecular basis underlying metastasis and recurrence is essential for advancing therapeutic development. The present study examines the contribution of hyaluronan-mediated motility receptor (HMMR) to HCC progression and its clinical implications.</p> Methods <p>Eighty paired HCC tumor and adjacent non-tumor tissues were obtained from patients who underwent radical resection. HMMR expression was evaluated by immunohistochemistry, Western blotting, and quantitative real-time PCR (qPCR). Kaplan–Meier and Cox regression analyses were employed to determine the association of HMMR expression with overall survival (OS) and recurrence-free survival (RFS). Functional assays were performed in Huh7 and Hep3B cells with HMMR knockdown or overexpression, including CCK-8 assays for proliferation, Transwell assays for migration and invasion, and Western blotting/qPCR for assessing epithelial–mesenchymal transition (EMT) markers (E-cadherin, N-cadherin, vimentin) and Wnt/β-catenin signaling components (GSK-3β, β-catenin, cyclin D1, c-myc). A subcutaneous xenograft model in nude mice was established to evaluate the effect of HMMR on tumor growth in vivo. Gene set variation analysis (GSVA) and molecular docking were applied to investigate HMMR-related pathways and potential protein–protein interactions.</p> Results <p>HMMR expression was markedly elevated in HCC tissues compared with adjacent tissues (<i>p</i> &lt; 0.001) at both mRNA and protein levels. Patients with high HMMR expression exhibited reduced median OS (27.8 vs. 32.3&#xa0;months, <i>p</i> = 0.012) and RFS (9.6 vs. 12.6&#xa0;months, <i>p</i> = 0.017). In vitro experiments demonstrated that HMMR silencing suppressed Huh7/Hep3B cell proliferation, migration (<i>p</i> &lt; 0.01), and invasion (<i>p</i> &lt; 0.001), while increasing E-cadherin and GSK-3β expression and reducing N-cadherin, vimentin, β-catenin, cyclin D1, and c-myc. Conversely, HMMR overexpression produced opposite effects. In xenograft models, tumors with HMMR knockdown displayed slower growth. GSVA indicated a positive correlation of HMMR expression with EMT and Wnt/β-catenin signaling, and molecular docking confirmed the binding capacity of HMMR to GSK-3β and β-catenin. Mechanistic analysis showed that HMMR suppressed GSK-3β phosphorylation activity, limiting β-catenin ubiquitination and degradation, thereby activating Wnt/β-catenin signaling and driving EMT.</p> Conclusions <p>HMMR stabilizes β-catenin by suppressing GSK-3β phosphorylation activity, which reduces β-catenin ubiquitination and degradation. Knocking down HMMR enhances GSK-3β expression and its degradative effect on β-catenin, thereby lowering β-catenin protein levels.</p>

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Hyaluronan-mediated motility receptor regulating the Wnt/β-catenin signaling resulting in hepatocellular carcinoma by inhibiting the phosphorylation activity of GSK-3β

  • 期刊论文

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  • 发表日期：

    2025年10月30日

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  • Yumei Zhang,
  • Zhiming Zhang,
  • Zongcai Yan,
  • Meiling He,
  • Xiuwen Wang

摘要

Background

Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a major global health burden due to its aggressive metastatic behavior and poor prognosis. Clarification of the molecular basis underlying metastasis and recurrence is essential for advancing therapeutic development. The present study examines the contribution of hyaluronan-mediated motility receptor (HMMR) to HCC progression and its clinical implications.

Methods

Eighty paired HCC tumor and adjacent non-tumor tissues were obtained from patients who underwent radical resection. HMMR expression was evaluated by immunohistochemistry, Western blotting, and quantitative real-time PCR (qPCR). Kaplan–Meier and Cox regression analyses were employed to determine the association of HMMR expression with overall survival (OS) and recurrence-free survival (RFS). Functional assays were performed in Huh7 and Hep3B cells with HMMR knockdown or overexpression, including CCK-8 assays for proliferation, Transwell assays for migration and invasion, and Western blotting/qPCR for assessing epithelial–mesenchymal transition (EMT) markers (E-cadherin, N-cadherin, vimentin) and Wnt/β-catenin signaling components (GSK-3β, β-catenin, cyclin D1, c-myc). A subcutaneous xenograft model in nude mice was established to evaluate the effect of HMMR on tumor growth in vivo. Gene set variation analysis (GSVA) and molecular docking were applied to investigate HMMR-related pathways and potential protein–protein interactions.

Results

HMMR expression was markedly elevated in HCC tissues compared with adjacent tissues (p < 0.001) at both mRNA and protein levels. Patients with high HMMR expression exhibited reduced median OS (27.8 vs. 32.3 months, p = 0.012) and RFS (9.6 vs. 12.6 months, p = 0.017). In vitro experiments demonstrated that HMMR silencing suppressed Huh7/Hep3B cell proliferation, migration (p < 0.01), and invasion (p < 0.001), while increasing E-cadherin and GSK-3β expression and reducing N-cadherin, vimentin, β-catenin, cyclin D1, and c-myc. Conversely, HMMR overexpression produced opposite effects. In xenograft models, tumors with HMMR knockdown displayed slower growth. GSVA indicated a positive correlation of HMMR expression with EMT and Wnt/β-catenin signaling, and molecular docking confirmed the binding capacity of HMMR to GSK-3β and β-catenin. Mechanistic analysis showed that HMMR suppressed GSK-3β phosphorylation activity, limiting β-catenin ubiquitination and degradation, thereby activating Wnt/β-catenin signaling and driving EMT.

Conclusions

HMMR stabilizes β-catenin by suppressing GSK-3β phosphorylation activity, which reduces β-catenin ubiquitination and degradation. Knocking down HMMR enhances GSK-3β expression and its degradative effect on β-catenin, thereby lowering β-catenin protein levels.