Dear Editor,
We appreciate Dr. Yang and colleagues for their insightful comments on our study investigating GULP PTB domain-containing engulfment adaptor 1 (GULP1) as a diagnostic and prognostic biomarker for hepatocellular carcinoma (HCC) [
1,
2]. Their letter highlights several key points that we are pleased to address, focusing strictly on the issues they raised.
Dr. Yang et al. noted the seemingly paradoxical role of GULP1, which has been reported as a tumor suppressor in other malignancies, versus its pro-oncogenic behavior in HCC [
2-
4]. Indeed, GULP1 is the human homolog of the
C. elegans gene
ced-6, and its function in engulfing apoptotic cells is evolutionarily conserved , known to mediate processes like Eph/ephrin trogocytosis in cooperation with Tiam2 and dynamin [
5,
6]. Consistent with this role, GULP1 has been considered a tumor suppressor in other cancers, in which it is frequently downregulated (for example, via promoter hypermethylation in urothelial carcinoma) [
4]. However, as Dr. Yang correctly pointed out, our findings in HCC reveal a strikingly different scenario. In our study, GULP1 was markedly upregulated in HCC tissues and actively drove oncogenic processes. Notably, elevated GULP1 enhanced β-catenin signaling and promoted epithelial–mesenchymal transition, processes associated with cancer invasion and metastasis . This mechanistic link is supported by our experimental data showing that GULP1 stabilizes active ARF GTPase 6 (ARF6), and that knocking down ARF6 markedly diminished GULP1-driven nuclear translocation of β-catenin. An important point raised in their letter is whether GULP1-driven β-catenin activation operates independently of other oncogenic pathways. Previous studies have suggested that β-catenin signaling in various liver diseases is often influenced by crosstalk with PI3K/AKT and MAPK pathways [
7-
9]. Given that metabolic reprogramming has been reported as a key driver of β-catenin-induced oncogenesis in HCC [
10], further research is needed to determine whether GULP1 contributes to these metabolic alterations and whether it interacts with additional oncogenic regulators to enhance tumor progression.
Another point raised by Dr. Yang and colleagues is the diagnostic utility of GULP1 relative to alpha-fetoprotein (AFP), the current standard serum marker for HCC [
11]. We reported that serum GULP1 levels outperformed AFP in detecting early-stage HCC and in predicting post-treatment recurrence, demonstrating superior sensitivity and specificity in our cohorts. We concur with Dr. Yang’s recognition that GULP1’s superior performance suggests it could potentially complement or even replace AFP in HCC surveillance. Moreover, GULP1 appeared to perform robustly across HCC cases of diverse etiologies while remaining low in non-malignant liver conditions, indicating it is a broadly applicable marker. Nonetheless, as Dr. Yang and colleagues noted, although GULP1 shows promising specificity, its modest area under the curve suggests it may not be sufficient alone. We agree that combining GULP1 with other markers, such as AFP or glypican-3, may improve diagnostic accuracy, aligning with the broader consensus on multi-biomarker strategies [
12]. Future large-scale studies will be also essential to confirm the added benefit of such a multi-marker panel [
13,
14]. We also acknowledge the importance of establishing a standardized cutoff value for serum GULP1 to maximize its clinical utility. In our study, we determined an optimal threshold that balanced sensitivity and specificity. Notably, for a screening setting, prioritizing high sensitivity (even at some cost to specificity) may be desirable given the paramount importance of detecting HCC at an early stage. Ongoing analyses in larger patient cohorts will help refine this cutoff and validate its performance.
Dr. Yang’s letter also mentioned the prognostic significance of GULP1 and its potential role in guiding therapy. We confirmed that GULP1 expression correlates with a higher risk of HCC recurrence after curative treatment, independent of traditional clinicopathological factors. Patients with elevated tumor (and serum) GULP1 had significantly shorter recurrence-free survival, underscoring GULP1’s value as an independent predictive biomarker for post-treatment outcomes. We agree with Dr. Yang et al. that the ability to monitor GULP1 in blood (a “liquid biopsy”) is particularly attractive. In fact, our study highlighted the potential of serum GULP1 as a minimally invasive tool for close surveillance, enabling earlier detection of recurrence and disease progression. A blood test for GULP1 could allow clinicians to track tumor dynamics in real time after surgery or ablation, so that any rising trend might trigger prompt diagnostic imaging or intervention. This approach aligns with the goal of more personalized and proactive HCC patient management.
In summary, we are grateful to Dr. Yang and colleagues for their thoughtful appraisal of our work. By addressing their points, we reiterate that GULP1 plays a unique and critical role in HCC, functioning contrary to its tumor-suppressive image in other cancers by instead promoting HCC progression. Its strong performance as a blood-based biomarker—exceeding the current standard AFP—and its association with tumor recurrence position GULP1 as a promising tool for improving HCC management. We fully agree that translating this discovery into clinical use will require careful, large-scale validation. Guided by Dr. Yang’s valuable insights, we remain committed to advancing GULP1 from bench to bedside, hoping that it will contribute to earlier detection of HCC and more personalized therapeutic strategies for our patients.
FOOTNOTES
-
Authors’ contribution
H.S.K., S.S.K., J.Y.C. and J.W.E. drafted and approved the manuscript.
-
Acknowledgements
This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republ ic of Korea (grant number HR21C1003), and by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (MSIT), Republic of Korea (grant numbers RS-2022-NR070489 and RS-2023-00210847).
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
GULP PTB domain containing engulfment adaptor 1
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