Dear Editor,
The recent study of GULP1 as a prognostic biomarker for hepatocellular carcinoma (HCC) provides valuable insights into the complex mechanisms underlying HCC recurrence and metastasis. Using advanced machine learning techniques, the researchers identified a 15-gene recurrence risk score model, with GULP1 emerging as a prominent marker for predicting recurrence [
1]. Despite these promising results, the study also provides avenues for further exploration and refinement.
The role of GULP1 in HCC is particularly compelling, as it differs from its traditionally recognized tumor suppressor function in other malignancies. In HCC, GULP1 appears to function as an oncogene, promoting β-catenin activation and facilitating epithelial-mesenchymal transition (EMT), processes essential for tumor progression and recurrence. This observation is consistent with the growing body of evidence that cancer-associated genes have context-dependent roles. For example, GULP1 downregulation in ovarian cancer is associated with tumor progression, whereas its overexpression in HCC accelerates metastasis, underscoring the critical influence of the tumor microenvironment on gene function [
2]. The study further elucidates GULP1’s involvement in the Wnt/β-catenin signaling pathway, a critical driver of EMT that enhances the migratory and invasive capabilities of cancer cells. By stabilizing β-catenin and affecting its subcellular localization, GULP1 enhances the invasive phenotype, providing critical insight into its potential role as a prognostic biomarker for recurrence in HCC, particularly in cases of advanced disease. This dual functionality of GULP1 requires a nuanced interpretation of its role in different cancers and warrants further validation in diverse clinical cohorts.
The diagnostic and prognostic potential of GULP1 is another important aspect of this study. By analyzing tissue and serum samples from HCC patients, the study demonstrates that GULP1 expression is significantly elevated in tumor tissues compared to non-tumor tissues. More importantly, serum levels of GULP1 showed higher accuracy than traditional biomarkers such as alpha-fetoprotein, particularly in distinguishing early stage HCC from other liver diseases such as cirrhosis and hepatitis. These findings are consistent with previous studies suggesting that liquid biopsy-based markers could revolutionize early detection and monitoring of cancer by providing a less invasive alternative to traditional tissue biopsies [
3]. However, while the study reports promising diagnostic performance for GULP1, there are some limitations that should be addressed. The modest area under the curve values for GULP1, particularly in tissue samples, indicate that its diagnostic utility is not yet on par with more established biomarkers. Further validation in larger, independent cohorts is needed to confirm the reproducibility of these findings in diverse populations. In addition, the combination of GULP1 with other biomarkers or molecular signatures may improve its diagnostic performance, as suggested by the results of the study showing increased positivity rates when α-fetoprotein and GULP1 were used together. The combination of multiple biomarkers, as explored by Zhou et al. [
3] (e.g., glypican-3), may offer improved specificity and sensitivity for HCC detection.
The mechanistic insights provided by the study—in particular the involvement of GULP1 in the regulation of β-catenin, ADP-ribosylation factor 6 (ARF6) and transcription factor 3—contribute significantly to our understanding of HCC progression. The study proposes a model in which GULP1 stabilizes ARF6 GTP, facilitating β-catenin nuclear translocation and transcriptional activation, thereby promoting oncogenic processes. This interaction highlights a potential therapeutic target for HCC. Several studies have highlighted the importance of β-catenin in liver cancer, and targeting this pathway may offer new therapeutic opportunities for the treatment of recurrent HCC [
4,
5]. Furthermore, the observation that suppression of GULP1 in HCC cells significantly reduces their proliferation, migration and invasion supports the idea that GULP1 may be an attractive target for therapeutic intervention. However, the results of the study are still preliminary and a more detailed mechanistic understanding is needed. While the authors provide compelling evidence for the involvement of GULP1 in HCC progression, it would be beneficial to explore how GULP1 interacts with other key signaling pathways, such as those involving PI3K/AKT or MAPK, which are also known to play critical roles in liver cancer. In addition, investigating the potential crosstalk between GULP1 and other oncogenic pathways in HCC may reveal novel therapeutic targets.
In conclusion, this study provides compelling evidence for the role of GULP1 as both a prognostic marker and an oncogene in HCC, providing new insights into the molecular mechanisms of HCC recurrence and metastasis. While the findings are promising, additional research is needed to validate the diagnostic and prognostic utility of GULP1 in larger patient cohorts and to further explore its therapeutic potential.
FOOTNOTES
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Acknowledgements
Yunnan Province High-Level Scientific and Technological Talents and Innovation Team Selection Special Project (202405AC350067).
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Authors’ contributions
Juan Yang wrote the manuscript, Xinyi Li provided methodological and theoretical support, and Sheng Zheng revised the manuscript and provided financial support.
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Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
ADP-ribosylation factor 6
epithelial-mesenchymal transition
REFERENCES
- 1. Kim HS, Yoon JH, Choi JY, Yoon MG, Baek GO, Kang M, et al. GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma. Clin Mol Hepatol 2025;31:914-934.
- 2. Maldonado L, Brait M, Izumchenko E, Begum S, Chatterjee A, Sen T, et al. Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1. Cancer Lett 2018;433:242-251.
- 3. Zhou F, Shang W, Yu X, Tian J. Glypican-3: a promising biomarker for hepatocellular carcinoma diagnosis and treatment. Med Res Rev 2018;38:741-767.
- 4. Dai W, Shen J, Yan J, Bott AJ, Maimouni S, Daguplo HQ, et al. Glutamine synthetase limits β-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1. J Clin Invest 2022;132:e161408.
- 5. Wang J, Yu H, Dong W, Zhang C, Hu M, Ma W, et al. N6-methyladenosine-mediated up-regulation of FZD10 regulates liver cancer stem cells’ properties and lenvatinib resistance through WNT/β-catenin and hippo signaling pathways. Gastroenterology 2023;164:990-1005.
Citations
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- Correspondence to letter to the editor on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”
Hyung Seok Kim, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun
Clinical and Molecular Hepatology.2026; 32(1): e103. CrossRef - Correspondence to editorial on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”
Soon Sun Kim, Hyung Seok Kim, Jae Youn Cheong, Jung Woo Eun
Clinical and Molecular Hepatology.2026; 32(1): e72. CrossRef
