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RIBOSOMAL PROTEIN RPS8 PROMOTES HEPATOCELLULAR CARCINOMA METASTASIS VIA UPREGULATING ISG15 TO STABILIZE NEUTROPHIL EXTRACELLULAR TRAP RECEPTOR CCDC25

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Introduction

Liver cancer ranks as the sixth most common malignant tumor worldwide and the third leading cause of cancer-related deaths. Hepatocellular carcinoma (HCC), accounting for approximately 90% of primary liver cancers, is among the most lethal malignancies, with a mortality-to-incidence ratio as high as 0.92. Metastasis remains a pivotal determinant of HCC patient prognosis and therapeutic efficacy, making in-depth exploration of its underlying mechanisms a critical foundation for improving clinical outcomes. Ribosomes, composed of ribosomal RNA (rRNA) and ribosomal proteins (RPs), are central to protein synthesis. Emerging evidence highlights that ribosomal heterogeneity influences tumor biology through differentially regulating protein translation. However, the specific mechanisms by which ribosomal proteins contribute to HCC metastasis remain poorly characterized, underscoring a significant gap in oncological research.

Aims & Methods

We performed a screen for ribosomal genes associated with survival in HCC patients using multiple databases through a comprehensively bioinformatics analysis. We estimated the correlation between RPS8 expression and clinicopathological features of patients in HCC. We explored the biological function of RPS8 in HCC cells via lentiviral in vitro. We further assessed the tumorigenicity of RPS8 using both subcutaneous tumor formation in nude mouse and orthotopic liver tumorigenesis in NCG mouse. multi-omics were applied for exploring the mechanism of RPS8 in HCC.

Results

Comprehensive pathological evaluation of HCC clinical specimens revealed overexpression of RPS8 in tumor tissues, which exhibited significant associations with higher tumor stage, poorly differentiated histology , microvascular invasion,and reduced overall survival.Functional studies demonstrated that knockdown of RPS8 suppressed proliferation, migration, and invasion in HCC cell lines . Overexpression of RPS8 could enhance the malignant behavior of HCC cells. Moreover, RPS8 depletion reduced subcutaneous tumor volume and orthotopic liver tumor metastasis to lungs. Mechanistically, proteomic analysis and RIP-seq revealed interferon-stimulated gene 15 (ISG15) exhibited the most significant downregulation at the protein level upon RPS8 knockdown and RPS8 directly binds to ISG15 mRNA. GO and KEGG analysis indicate that RPS8 promotes HCC invasion and metastasis by modulating cell motility and migration. Among the top five differentially expressed proteins, CCDC25, a neutrophil extracellular trap (NET) repceptor, exhibited the most significant downregulation upon RPS8 knockdown. ISG15 can bind with target proteins to form ISGlation, thus preventing the ubiquitinlation. Bioinformatic predictions have identified six potential ubiquitination modification sites in CCDC25. Additionally, molecular docking analyses suggest the presence of potential ubiquitination modification sites within the binding interface between ISG15 and CCDC25. We then performed CCDC25 overexpression in RPS8-knockdown HCC cells and CCDC25 knockout in RPS8-overexpressing HCC cells. Downregulation or upregulation of CCDC25 partially reversed the oncogenic effects of RPS8 respectively, supporting CCDC25 as a critical downstream mediator of RPS8-driven HCC progression. Finally, we found that NETs from HCC patients could promote in vivo metastasis of control cells, but showed less efficacy in RPS8-knockdown cells.

Conclusion

Ribosomal protein RPS8 promotes HCC metastasis through upregulating ISG15 to stabilize NETs receptor CCDC25 protein. These findings provide a promising therapeutic strategy targeting .

References

1.Kang J, Brajanovski N, Chan KT et al. Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy. Signal Transduction and Targeted Therapy 2021; 6.
2. Larionova TD, Bastola S, Aksinina TE et al. Alternative RNA splicing modulates ribosomal composition and determines the spatial phenotype of glioblastoma cells. Nature Cell Biology 2022; 24:1541-1557.
3.Kang JA, Kim YJ, Jeon YJ. The diverse repertoire of ISG15: more intricate than initially thought. Experimental & Molecular Medicine 2022; 54:1779-1792.
4.Yang L, Liu Q, Zhang X et al. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25. Nature 2020; 583:133-138.
5.Zhan X, Wu R, Kong XH et al. Elevated neutrophil extracellular traps by HBV‐mediated S100A9‐TLR4/RAGE‐ROS cascade facilitate the growth and metastasis of hepatocellular carcinoma. Cancer Communications 2022; 43:225-245.

RIBOSOMAL PROTEIN RPS8 PROMOTES HEPATOCELLULAR CARCINOMA METASTASIS VIA UPREGULATING ISG15 TO STABILIZE NEUTROPHIL EXTRACELLULAR TRAP RECEPTOR CCDC25

Qin Tang 1, Xueyin Chen 1, Yongjun Zhu 1, Jian Gao 1, Song He 1, Zhihang Zhou 1

1 The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

Event

UEG Week Berlin 2025

Topics

Hepatobiliary Immunology Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Bench to bedside and beyond frontiers in HCC

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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CCC: Molecular targeted therapies

Arndt Vogel 1

1 Medizin. Hochschule Hannover, Hannover, Canada

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Hepatobiliary Mechanisms & Personalised Medicine Radiology & Imaging

Session

Advancement in management of primary liver tumors

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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GUT MYCOBIOME SIGNATURES PREDICT NEOADJUVANT IMMUNOCHEMOTHERAPY RESPONSE IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA: A MACHINE LEARNING APPROACH WITH EXPERIMENTAL VALIDATION

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Introduction

Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis despite advances in neoadjuvant immunochemotherapy (NICT). With highly variable treatment responses, identifying reliable predictive biomarkers remains crucial. While gut microbiome influences on immunotherapy efficacy are increasingly recognized, the specific role of the fungal microbiome (mycobiome) in NICT outcomes for ESCC remains unexplored, representing a significant gap in developing personalized treatment strategies.

Aims & Methods

This study aimed to characterize gut mycobiome signatures in ESCC patients and develop fungal biomarker-based predictive models for NICT response. We conducted ITS2 sequencing on 136 fecal samples collected from 68 ESCC patients (pre- and post-NICT) and 19 healthy controls (HC). Patients were stratified as responders (R, n=26) or non-responders (NR, n=42) based on tumor regression grade (TRG) scores. We performed comprehensive analyses of mycobiome diversity, composition, co-occurrence networks, and functional pathways across groups. The Boruta algorithm was employed for feature selection to identify fungal biomarkers, followed by multilayer perceptron (MLP) machine learning with five-fold cross-validation to develop predictive models. Additionally, ESCC xenograft models were established to investigate gut mycobiome-immune interactions through fecal microbiota transplantation (FMT) and targeted fungal manipulation experiments.

Results

ESCC patients demonstrated significant mycobiome dysbiosis compared to healthy controls, characterized by reduced fungal alpha diversity and distinct beta diversity patterns. At baseline, ESCC patients showed enrichment of Rhodotorula minuta, Actinomucor elegans, and several Candida species. Responders exhibited significantly higher baseline fungal diversity than non-responders, with enrichment of Meyerozyma, Candida boidinii, Trichosporon dermatis, and Cryptococcus species, whereas non-responders showed predominance of Saccharomyces, Nakaseomyces, and pathogenic Candida species (C. glabrata, C. parapsilosis, C. albicans). Responders also displayed more complex, stable fungal co-occurrence networks with higher density and clustering coefficients. Post-NICT, both groups showed partial recovery of mycobiome diversity, with significant increases in beneficial fungal taxa. Functional pathway analysis revealed distinct metabolic profiles between responders and non-responders. Using the Boruta algorithm, we identified 23 genus-level and 22 species-level fungal biomarkers that demonstrated high predictive value. The MLP model based on genus-level markers achieved AUCs of 90.2% (training) and 91.9% (test), while the species-level model showed comparable performance. In animal experiments, mice receiving R-FMT exhibited reduced tumor growth and enhanced CD8+ T cell infiltration compared to NR-FMT recipients. Notably, Candida boidinii supplementation synergized with anti-PD-1 therapy, while Saccharomyces depletion enhanced treatment sensitivity.

Conclusion

Our findings establish the gut mycobiome as a powerful predictor of NICT response in ESCC, with machine learning models achieving >90% accuracy using fungal biomarkers. Experimental validation not only confirms mechanistic links between specific fungi and antitumor immunity but also demonstrates that targeted mycobiome modulation can enhance immunotherapy efficacy. This dual approach of prediction and intervention offers a novel framework for precision oncology in ESCC, potentially transforming clinical decision-making and treatment outcomes in this challenging malignancy.

References

1. Li J, Xu J, Zheng Y, et al. Esophageal cancer: Epidemiology, risk factors and screening. Chin J Cancer Res. 2021; 33(5): 535-547.
2. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012; 366(22): 2074-2084.
3. Schroeder W, Ghadimi M, Schloesser H, et al. Long-Term Outcome After Histopathological Complete Response with and Without Nodal Metastases Following Multimodal Treatment of Esophageal Cancer. Ann Surg Oncol. 2022.
4. Rosner S, Liu C, Forde PM, Hu C. Association of Pathologic Complete Response and Long-Term Survival Outcomes Among Patients Treated With Neoadjuvant Chemotherapy or Chemoradiotherapy for NSCLC: A Meta-Analysis. JTO Clin Res Rep. 2022; 3(9): 100384.
5. Coker OO, Nakatsu G, Dai RZ, et al. Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. Gut. 2019; 68(4): 654-662.
6. Dohlman AB, Klug J, Mesko M, et al. A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal and lung tumors. Cell. 2022; 185(20): 3807-3822.
7. Wurster S, Albert ND, Kontoyiannis DP. Candida auris Bloodstream Infection Induces Upregulation of the PD-1/PD-L1 Immune Checkpoint Pathway in an Immunocompetent Mouse Model. Msphere. 2022; 7(2): e81721.

GUT MYCOBIOME SIGNATURES PREDICT NEOADJUVANT IMMUNOCHEMOTHERAPY RESPONSE IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA: A MACHINE LEARNING APPROACH WITH EXPERIMENTAL VALIDATION

le liu 1, Liping Liang 2, Shijie Mai 3

1 Zhujiang Hospital, Southern Medical University, Guangzhou, China

2 Guangzhou First People's Hospital, Guangzhou, China

3 Nanfang Hospital, Southern Medical University, Guangzhou, China

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Gut Microbiota Immunology Mechanisms & Personalised Medicine Oesophagus

Submission format

Abstract

Session

Oncobiome

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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ACLF: When to be concerned?

Christiana Graf 1

1 LMU Klinikum, Munich, Germany

Event

UEG Week Berlin 2025

Topics

Colorectal Hepatobiliary Pancreas

Session

Predicting disease severity

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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SAFETY AND EFFICACY OF EXTENDED SURVEILLANCE INTERVALS FOLLOWING COLORECTAL ESD: AN INTERNATIONAL MULTICENTER STUDY

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Introduction

Post-ESD surveillance guidelines remain heterogeneous, with many centers favoring early surveillance colonoscopy (SC) despite low recurrence rates after curative resection. This study aimed to evaluate the safety and outcomes of delayed SC after R0 colorectal ESD for benign lesions and to identify risk factors for metachronous advanced neoplasia.

Aims & Methods

We retrospectively analyzed 1,097 patients who underwent colorectal ESD between 2013 and 2021. Clinical, procedural, and histological characteristics were recorded. Among 778 patients with available surveillance data, outcomes were compared between those who had early SC (<12 months) and those with delayed SC (>24 months). Rates of recurrence, advanced neoplasia, and colorectal cancer were assessed. Risk factors for metachronous advanced neoplasia were evaluated via univariate and multivariate analysis.

Results

Mean patient age was 74.3 ± 10.8 years; 54.1% were male. En bloc and R0 resection rates were 95.8% and 83.3%, respectively. Among patients with surveillance data, 82.6% underwent early SC, and 17.4% had late-only SC. The rate of advanced adenoma at first SC was low and comparable between early and late groups (3.9% vs. 6.7%, p = 0.167). The overall rate of metachronous advanced adenoma was 6.5%, with no significant difference between early and late strategies (6.1% vs. 8.9%, p = 0.25). All four colorectal cancers were detected in the early group; none occurred in the late-only group. Recurrence on the ESD scar was rare (1.5% overall), and no late recurrences occurred after a normal SC1. The only significant predictor of metachronous advanced neoplasia was the number of synchronous lesions at index colonoscopy (OR 1.16, 95% CI 1.07–1.27; p < 0.01).

Conclusion

Delayed surveillance colonoscopy 3 years after R0 colorectal ESD for benign lesions appears safe and effective in selected patients. The multiplicity of synchronous lesions could guide risk stratification. These findings support extending SC intervals after curative ESD, with potential to reduce unnecessary procedures.

References

Pimentel-Nunes P, Libânio D, Bastiaansen BAJ, Bhandari P, Bisschops R, Bourke MJ, et al. Endoscopic submucosal dissection for superficial gastrointestinal lesions: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2022. Endoscopy. juin 2022;54(6):591‑622.
Dai M, Xiao X, Guo CLT, Lui RN, Yip HC, Chu S, et al. The Long‐Term Risk of Metachronous Advanced Adenoma Recurrence After Endoscopic Submucosal Dissection for Colorectal Neoplasia: A Propensity‐Score Matched Longitudinal Cohort With 5‐Year Follow‐Up. United Eur Gastroenterol J. 21 déc 2024;13(2):210‑9.
Yoshida N, Naito Y, Siah KTH, Murakami T, Ogiso K, Hirose R, et al. High incidence of metachronous advanced adenoma and cancer after endoscopic resection of colon polyps ≥20 mm in size. Dig Endosc Off J Jpn Gastroenterol Endosc Soc. mars 2016;28(2):194‑202.