Dear Editor,
We thank Wang and colleagues for their comprehensive and constructive reply to our correspondence on their hepatocellular carcinoma (HCC) MET-TRIB3 axis study [
1-
3]. We appreciate the authors’ willingness to integrate our observations on the immune microenvironment and molecular subgroup stratification into their future research.
First, we particularly agree with the authors’ emphasis on the need to move “from bulk correlations to causal mechanisms.” Clarifying how TRIB3 shapes the immunosuppressive microenvironment, whether through chemokines, antigen presentation pathways, or broader immune regulatory networks, will greatly strengthen the rationale for combined immunotherapy strategies.
Second, the authors’ plan to conduct comprehensive molecular and pathological profiling (including HBV status, differentiation grade, TNM staging, and TP53/CTNNB1 mutations) and establish PDX models based on subgroup characteristics is highly valuable. Rigorous validation of TRIB3 dependency in the “HBV-positive/poorly differentiated/TP53-mutant” subgroup may help explain heterogeneous patient responses to MET-targeted or combination therapies and provide reliable evidence for patient stratification.
Finally, the authors mentioned that their preliminary experiments showed no change in TRIB3 expression after transient transfection of constitutively active CTNNB1 mutants in Hep3B cells. This negative finding is itself informative, suggesting that CTNNB1-mediated TRIB3 regulation may require specific cellular contexts or co-activating signals.
Recent studies in colorectal cancer have shown that TRIB3 interacts with β-catenin and TCF4 in intestine cells to increase expression of genes associated with cancer stem cells [
4]. Whether similar mechanisms operate in HCC, and whether they depend on specific co-factors or pathway co-activation, remains to be systematically investigated. Clarifying the molecular determinants of CTNNB1-TRIB3 cross-talk is important for understanding TRIB3 regulation beyond MET signaling and for identifying patient subgroups in whom TRIB3 remains a viable therapeutic target even without MET pathway activation. Meanwhile, combined MET/Wnt inhibition represents an attractive therapeutic strategy, particularly for tumors with alterations in both pathways. However, due to on-target toxicities and the essential role of Wnt signaling in normal tissue homeostasis, clinical development of Wnt inhibitors in HCC has faced considerable challenges [
5]. In this context, targeting downstream convergence points like TRIB3 may offer a more feasible approach with potentially broader applicability across different molecular subtypes.
We sincerely appreciate the authors’ reply and look forward to the results of these future studies and their potential to improve outcomes for hepatocellular carcinoma patients. We believe this exchange highlights the value of scholarly dialogue in refining hypotheses and accelerating translational research progress in hepatocellular carcinoma.
FOOTNOTES
-
Authors’ contributions
All authors contributed to this study at different levels. All authors read and approved the final version. Study concept and design (Lei Wu and Yan Zheng); drafting of the manuscript (Lei Wu).
-
Acknowledgements
This study was funded by the Shandong Provincial Natural Science Foundation (ZR2022QH245); Jinan Municipal Special Fund for High-level Talents in Medical and Health Industry (202412). Scientific Research Foundation for the Introduced Talents of Jinan Central Hospital (YJRC2022003/YJRC2022005).
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
REFERENCES
- 1. Wang T, Rao D, Fu C, Sun Z, Luo Y, Lu J, et al. MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation. Clin Mol Hepatol 2025;31:1032-1057.
- 2. Wang T, Huang W, Xia L. Correspondence to letter to the editor on “MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation”. Clin Mol Hepatol 2026;32:e405-e408.
- 3. Wu L, Liu N, Song P, Sun M. Extending MET-TRIB3 axis research in hepatocellular carcinoma: Immune contexture and patient subgroups: Letter to the editor on “MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation”. Clin Mol Hepatol 2026;32:e279-e282.
- 4. Hua F, Shang S, Yang YW, Zhang HZ, Xu TL, Yu JJ, et al. TRIB3 interacts with β-catenin and TCF4 to increase stem cell features of colorectal cancer stem cells and tumorigenesis. Gastroenterology 2019;156:708-721.e15.
- 5. Xu C, Xu Z, Zhang Y, Evert M, Calvisi DF, Chen X. β-Catenin signaling in hepatocellular carcinoma. J Clin Invest 2022;132:e154515.
Citations
Citations to this article as recorded by
