Dear Editor,
We sincerely appreciate Dr. Lei Wu and colleagues for their thoughtful and insightful letter regarding our study “MET promotes hepatocellular carcinoma (HCC) development through the promotion of TRIB3-mediated FOXO1 degradation” [
1,
2]. Their work extends our original findings by integrating multi-omics datasets to explore the MET–TRIB3 axis in the context of tumor immune microenvironment, patient subgroup stratification, and cross-talk with alternative oncogenic pathways. This rigorous academic inquiry not only validates the clinical relevance of our research but also provides critical directions for translational advancement. We are grateful for this valuable exchange, which deepens our understanding of TRIB3’s oncogenic role and informs future therapeutic strategies.
Our original study established a core mechanism wherein MET signaling upregulates TRIB3 via the ERK–SP1 axis, leading to COP1-mediated FOXO1 degradation and subsequent HCC progression [
1]. Dr. Wu et al.’s letter enriches this framework with three key observations, each of which we address below with complementary data and planned investigations.
First, regarding the association between TRIB3 and the immunosuppressive tumor microenvironment: We fully endorse their CIBERSORT deconvolution analysis demonstrating a positive correlation between TRIB3 expression and regulatory T (Treg) cell infiltration in the TCGA-LIHC cohort. This intriguing observation aligns with the potential immunomodulatory role of TRIB3 [
3], and we plan to explore this further in future studies. Given that their analysis identifies a statistical association from bulk transcriptomics, establishing causal relationships will be a key focus of our upcoming research. We aim to design functional studies using TRIB3 knockout/overexpression HCC cell lines cocultured with peripheral blood mononuclear cells to directly assess whether TRIB3 regulates Treg cell migration and suppressive function. Additionally, future preclinical trials in orthotopic HCC mouse models with high Treg infiltration could evaluate the synergistic efficacy of TRIB3 silencing (via AAV8-shTRIB3) combined with anti-PD-1/PD-L1 inhibitors. These investigations would test the promising hypothesis proposed by Dr. Wu et al. that targeting the MET–TRIB3 axis can reverse immune suppression and enhance immune checkpoint inhibitor responsiveness.
Second, concerning TRIB3 dependency in specific HCC subgroups: We highly value their identification of the “HBV-positive + undifferentiated/poorly differentiated + TP53-mutant” subtype as a potential priority indication for TRIB3-targeted therapy, which is based on CRISPR screening data revealing strong TRIB3 dependency in the SNU398 cell line. In our clinical cohort of 75 HCC patients, we have analyzed TRIB3 expression in the context of TNM staging (stages 1+2 vs. 3+4) but did not perform subgroup analyses by tumor differentiation grade or HBV infection status. Notably, no significant difference in TRIB3 expression was observed between the early-stage (1+2) and advanced-stage (3+4) TNM subgroups. These unaddressed aspects—along with the lack of stratification by TP53 mutation status and exploration of combined molecular-clinical features—represent important directions for future research expansion. To validate this subgroup-specific dependency, we plan to expand our patient cohort with comprehensive molecular and pathological profiling (including HBV infection status, tumor differentiation grade, TNM staging, and TP53/CTNNB1 mutations), and systematically analyze the correlations of these individual and combined features with TRIB3 expression levels and patient prognostic outcomes. Additionally, establishing patient-derived xenograft (PDX) models from HCC patients—with subsequent focus on incorporating cases that are HBV-positive, poorly differentiated, and harbor TP53 mutations—is a key future goal. Such models will enable in-depth assessment of TRIB3 silencing efficacy within subgroup-specific contexts. While we recognize their observation is based on a single cell line, future preclinical and clinical analyses with expanded datasets will help provide more robust evidence to guide subgroup-specific treatment selection.
Third, regarding cross-talk between the MET–TRIB3 axis and the Wnt/β-catenin pathway: Dr. Wu et al.’s finding that TRIB3 can be activated by CTNNB1 mutations (in combination with RAS/EGFR/Akt) independently of MET is particularly impactful. In our original study, we focused on MET-mediated TRIB3 regulation via the ERK–SP1 axis but did not explore alternative drivers, nor have we analyzed CTNNB1 mutation status in our clinical cohort—an important unaddressed area highlighted by their work. Notably, our preliminary validation experiments showed that transient transfection of constitutively active CTNNB1 mutants in Hep3B cells did not alter TRIB3 expression1. While the CTNNB1 mutation frequency is reported to be 20–40% [
4,
5], we have not yet verified this frequency in our 75-patient cohort or explored correlations between CTNNB1 mutation status and TRIB3 expression. Future studies will first clarify the CTNNB1 mutation landscape in our expanded clinical cohort and systematically investigate the molecular mechanism underlying potential cross-talk between the Wnt/β -catenin pathway and MET–TRIB3 axis—such as whether TCF4/β-catenin directly transactivates TRIB3 (as reported in colorectal cancer [
6]) or if co-activation of RAS/EGFR/Akt is required for CTNNB1-mediated TRIB3 regulation. Additionally, we plan to evaluate the efficacy of combined MET/Wnt inhibition (using MET inhibitors [
7] + XAV939 [
8]) in HCC cell lines with defined CTNNB1 mutation status and future PDX models. Stratifying ongoing and upcoming prospective clinical trials of MET inhibitors by CTNNB1 mutation status will also be a priority, as this will help clarify whether this subgroup exhibits distinct responses to MET-targeted therapy.
We acknowledge the limitations of our original study, including the use of a MET/β-catenin-overexpressing HTVi model (which may not fully recapitulate tumor heterogeneity) and a focus on non-HBV-related HCC. To address these, future research will expand to PDX models with endogenous oncogenic alterations and include HBV-related HCC in our cohort to evaluate pathway conservation across etiologies.
In conclusion, Dr. Wu et al.’s letter provides critical translational insights that strengthen the clinical relevance of the MET–TRIB3 axis. Their work highlights the need to integrate immune contexture, molecular subtypes, and pathway cross-talk into therapeutic development. We are committed to advancing the aforementioned investigations and believe that our collective efforts will lead to more precise and effective treatments for HCC patients.
We sincerely thank Dr. Wu and colleagues for their valuable contributions to this field and for inspiring further exploration of the MET–TRIB3 axis.
FOOTNOTES
-
Authors’ contribution
Data collection and analysis: All authors. Manuscript drafting and revision: All authors.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
patient-derived xenograft
REFERENCES
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- 6. 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.
- 7. Guo R, Offin M, Brannon AR, Chang J, Chow A, Delasos L, et al. MET Exon 14-altered lung cancers and MET inhibitor resistance. Clin Cancer Res 2021;27:799-806.
- 8. Crespo M, Vilar E, Tsai SY, Chang K, Amin S, Srinivasan T, et al. Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing. Nat Med 2017;23:878-884.
Citations
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- Reply to correspondence on “MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation”
Lei Wu, Yan Zheng
Clinical and Molecular Hepatology.2026; 32(3): e445. CrossRef
