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OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human
Yosuke Ashizawa1, Satoshi Kuboki1, Hiroyuki Nojima1
1Department of General Surgery, Graduate School of Medicine Chiba University Chiba Japan.
Abstract:
Olfactomedin 4 (OLFM4) induces signal transducer and activator of transcription 3 (STAT3) activation by inhibiting gene associated with retinoid-interferon-induced mortality 19 (GRIM19), a strong STAT3 suppressor gene; however, the mechanisms of OLFM4 for regulating GRIM19-STAT3 cascade in hepatocellular carcinoma (HCC) remain unclear. The functions and regulations of OLFM4, GRIM19, and STAT3 activation in HCC progression were evaluated using surgical specimens collected from 111 HCC patients or 2 HCC cell lines in vitro. Moreover, the cancer stem cell-like property of OLFM4 mediated by leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), known as an intestinal stem cell marker, was investigated. OLFM4 was increased in HCC compared with adjacent liver tissue. The multivariate analysis revealed that high OLFM4 expression was an independent factor for poor prognosis. OLFM4 expression was negatively correlated with GRIM19 expression and positively correlated with STAT3 activation in HCC, thereby increasing cell cycle progression. OLFM4 knockdown in HCC cells increased GRIM19 expression and inhibited STAT3 activation; however, after double knockdown of GRIM19 and OLFM4, STAT3 activation decreased by OLFM4 knockdown was increased again. OLFM4 knockdown increased cell apoptosis, inhibited cell proliferation, and suppressed cancer stem cell-like property in HCC cells. The incidence of hematogenous recurrence was higher in HCC patients with high OLFM4 expression, suggesting that anoikis resistance of HCC was enhanced by OLFM4. In clinical cases, LGR5 expression and CD133 expression was correlated with OLFM4 expression in HCC, leading to poor patient prognosis. In vitro, LGR5 enhanced cancer stem cell-like property by up-regulating OLFM4 through the Wnt signaling pathway. Conclusion: OLFM4 is induced by the LGR5-Wnt signaling pathway and is strongly associated with aggressive tumor progression and poor prognosis in HCC by regulating STAT3-induced tumor cell proliferation and cancer stem cell-like property. Therefore, OLFM4 is a novel prognostic predictor and a potential therapeutic target for patients with HCC.
Insights
Olfactomedin 4 (OLFM4) promotes hepatocellular carcinoma (HCC) progression by inhibiting GRIM19 and activating STAT3. Targeting OLFM4 may improve HCC prognosis and treatment outcomes.
Area of Science:
- Hepatobiliary Medicine
- Cancer Biology
- Molecular Oncology
Background:
- Olfactomedin 4 (OLFM4) is implicated in hepatocellular carcinoma (HCC) pathogenesis.
- The precise mechanisms by which OLFM4 influences the GRIM19-STAT3 signaling axis in HCC are not fully understood.
- Cancer stem cell-like properties are crucial in HCC progression and recurrence.
Purpose of the Study:
- To elucidate the regulatory role of OLFM4 in the GRIM19-STAT3 pathway within HCC.
- To investigate the association between OLFM4, cancer stem cell markers (LGR5, CD133), and HCC patient prognosis.
- To evaluate OLFM4 as a potential prognostic biomarker and therapeutic target for HCC.
Main Methods:
- Analysis of OLFM4, GRIM19, and STAT3 expression in 111 HCC surgical specimens and HCC cell lines.
- In vitro experiments involving OLFM4 and GRIM19 knockdown to assess STAT3 activation and cellular behavior.
- Investigation of the LGR5-Wnt signaling pathway's role in OLFM4-mediated cancer stem cell properties.
Main Results:
- OLFM4 expression was significantly elevated in HCC tissues and correlated with poor prognosis.
- OLFM4 negatively regulated GRIM19 and positively modulated STAT3 activation, promoting cell cycle progression.
- OLFM4 knockdown reduced tumor cell proliferation, induced apoptosis, suppressed stem cell-like properties, and decreased recurrence incidence.
- LGR5 expression positively correlated with OLFM4 and CD133 expression, indicating poor prognosis.
Conclusions:
- OLFM4, induced by the LGR5-Wnt pathway, drives aggressive HCC progression and poor prognosis by enhancing STAT3-mediated proliferation and stem cell-like traits.
- OLFM4 serves as a novel prognostic predictor for HCC.
- OLFM4 represents a potential therapeutic target for HCC treatment.
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