A GYS2/p53 negative feedback loop restricts tumor growth in HBV-related hepatocellular carcinoma

Chen, S.-L.; Zhang, C. Z.; Liu, L.-L.; Lu, S.-X.; Pan, Y.-H.; Wang, C.-H.; He, Y.-F.; Lin, C.-S.; Yang, X.; Xie, D.; Yun, J.-P.

doi:10.1101/373761

Home/Archive/bioRxiv

bioRxiv · 10.1101/373761

A GYS2/p53 negative feedback loop restricts tumor growth in HBV-related hepatocellular carcinoma

Chen, S.-L.·Zhang, C. Z.·Liu, L.-L.·Lu, S.-X.·Pan, Y.-H.·Wang, C.-H.·He, Y.-F.·Lin, C.-S.·Yang, X.·Xie, D.·Yun, J.-P.

View original source ↗Export metadata ↓

Abstract

Hepatocarcinogenesis is attributed to the reprogramming of cellular metabolism as consequence of the alteration in metabolite-related gene regulation. Identifying the mechanism of aberrant metabolism is of great potential to provide novel targets for the treatment of hepatocellular carcinoma (HCC). Here, we demonstrated that glycogen synthase 2 (GYS2) restricted tumor growth in HBV-related HCC via a negative feedback loop with p53. Expression of GYS2 was significantly downregulated in HCC and correlated with decreased glycogen content and unfavorable patient outcomes. GYS2 overexpression suppressed, whereas GYS2 knockdown facilitated cell proliferation in vitro and tumor growth in vivo via modulating p53 expression. GYS2 competitively bound to MDM2 to prevent p53 from MDM2-mediated ubiquitination and degradation. Furthermore, GYS2 enhanced the p300-induced acetylation of p53 at K373/382, which in turn inhibited the transcription of GYS2 in the support of HBx/HDAC1 complex. In summary, our findings suggest that GYS2 serves as a prognostic factor and functions as a tumor suppressor in HCC. The newly identified HBx/GYS2/p53 axis is responsible for the deregulation of glycogen metabolism and represents a promising therapeutic target for the clinical management of HCC.\n\nSynopsisThis study elucidate the role of GYS2 in glycogen metabolism and the progression of HCC. The newly identified HBx/GYS2/p53 axis is responsible for the deregulation of glycogen metabolism and represents a promising therapeutic target for the clinical management of HCC.\n\nO_LIDecrease of GYS2 was significantly correlated with decreased glycogen content and unfavorable patient outcomes in a large cohort containing 768 patients with HCC.\nC_LIO_LIGYS2 overexpression suppressed, whereas GYS2 knockdown facilitated cell proliferation in vitro and tumor growth in vivo via modulating p53 signaling pathway.\nC_LIO_LIGYS2 competitively bound to MDM2 to prevent p53 from MDM2-mediated ubiquitination and degradation.\nC_LIO_LIGYS2 enhanced the p300-induced acetylation of p53 at Lys373/382, which in turn inhibited the transcription of GYS2 in the support of HBx/HDAC1 complex.\nC_LI

Source connections

Published article ↗

Explore related subjects

pathology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Chen, S.-L., Zhang, C. Z., Liu, L.-L., Lu, S.-X., Pan, Y.-H., Wang, C.-H., He, Y.-F., Lin, C.-S., Yang, X., Xie, D., Yun, J.-P.. 2018-07-20. A GYS2/p53 negative feedback loop restricts tumor growth in HBV-related hepatocellular carcinoma. https://doi.org/10.1101/373761

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Digital pathological classification of peripheral neuroblastic tumors across multi-continent cohorts

Peripheral neuroblastic tumors (pNTs) are embryonal tumors of neural crest origin with highly variable clinical behaviors, ranging from spontaneous regression to aggressive and fatal disease. The International Neuroblastoma Pathology Classification (INPC) defines four diagnostic categories and stratifies tumors into Favorable Histology (FH) or Unfavorable Histology (UH) group based on age-linked assessment of tumor differentiation/maturation and the Mitosis-Karyorrhexis Index (MKI). Prognostic distinction according to INPC offers significant prediction of clinical outcomes, with patients harboring FH tumors demonstrating longer overall and event-free survival than those with UH tumor. Here, we assembled the largest multi-continental whole-slide histology imaging dataset of pNTs to date, comprising 2,030 tumors from the United States, Canada, Australia, New Zealand, Germany and Japan. Using this dataset, we developed NB-PathAssist, a computational pathology framework for automated INPC-based classification from digitized whole-slide images. NB-PathAssist integrates foundation-model-based feature extraction with an archetype-guided SummaryMixing architecture that compresses whole-slide morphology into representative histologic tokens for tumor-level classification. To automate MKI assessment, we manually annotated 14,049 nuclei, classifying them as mitotic-karyorrhectic (MK) tumor cells, non-MK tumor cells, or non-tumor cells. The resulting model was applied to phenotype cells in whole-slide images across 1,649 tissue sections. Across geographically and institutionally diverse cohorts, NB-PathAssist reproducibly assessed key diagnostic features and generated prognostic classifications concordant with reference INPC annotations. The average balanced accuracy for classifying tumor categories, grade of neuroblastic differentiation, MKI and prognostic groups achieved 0.84, 0.86, 0.89 and 0.96, respectively. We packaged the NB-PathAssist algorithms into an end-to-end online platform for scalable and standardized AI-assisted assessment of pNTs.

pathology↗

bioRxiv2026

Epidemic Risks associated with high-temperature replicating infectious hematopoietic necrosis virus (IHNV) field isolates: from molecular characterization to host pathogen interactions

Infectious hematopoietic necrosis virus (IHNV) is a WOAH-notifiable pathogen responsible for severe acute disease in salmonids at temperatures ranging from 4 to 14{degrees}. At higher water temperatures, the disease is generally associated with reduced mortality and lower viral replication. In the context of climate change, rising water temperatures could favor the emergence of thermotolerant strains while representing a major physiological and metabolic stress potentially altering fish's immune responses. This study aims to characterize the impact of increasing water temperatures on IHNV replication and host-pathogen interactions. Following pre-screening, the replication kinetics of the reference strain N61 and two field isolates RtNag0a and SA-22 were characterized in EPC (Epithelioma Papulosum Cyprini) and RTG-2 (Rainbow trout gonad) cell lines at 14, 20 and 22{degrees}. Virulence and host-pathogen interactions were subsequently investigated in vivo in zebrafish (Zf) larvae using complementary microinjection and bath immersion infection models at 21.5 and 23.5{degrees}. In vitro studies revealed distinct thermal replication profiles, distinguishing thermosensitive from thermotolerant isolates, although these phenotypes were influenced by the cellular environment. The zebrafish model enabled the characterization of virulence and antiviral host responses associated with thermotolerant IHNV isolates. Notably, waterborne infection proved effective, contrasting with previous reports describing this exposure route as unsuitable for IHNV studies. These findings expand the growing list of emerging European IHNV genotypes capable of replicating at elevated temperatures (>20{degrees}) and establish zebrafish larvae as a relevant model for virulence assessment of field isolates. Together, these results provide valuable insights into the potential impact of climate warming on IHNV epidemiology and support efforts to predict and anticipate future outbreaks under changing environmental conditions.

pathology↗

bioRxiv2026

Arthroscopic Raman Probe Provides Biomarkers of TMJ Tissue Composition that Account for Tissue Function

Background: Temporomandibular joint (TMJ) disorders affect up to 25% of the population and may require diverse surgical interventions. However, intraoperative decision-making relies largely on visual assessment, which does not quantitatively characterize tissue composition or mechanical function. Raman spectroscopy offers a nondestructive approach to molecular-level tissue characterization, but its application to TMJ tissues remains unvalidated. Methods: An arthroscopy-compatible Raman probe was used to characterize mandibular condyles (n=15 porcine, n=11 human) and human articular discs (n=7). Raman-derived biomarkers associated with glycosaminoglycans (GAG), collagen (COL), water (H2O), and hydroxyapatite (HA) were evaluated against condylar indentation modulus and disc tensile modulus. Arthroscopic measurements in cadaveric TMJs assessed technical feasibility, while hyperspectral Raman imaging characterized spatial compositional distributions. Results: For condylar cartilage, combined GAG and H2O biomarkers accounted for 86% of the variation in indentation modulus (R2=0.86), compared with 4% for Outerbridge grading (R2=0.04). For articular discs, combined proline and water-associated biomarkers accounted for 88% of the variation in tensile modulus (R2=0.88). Raman spectra acquired in situ under simulated arthroscopic conditions were comparable in quality to ex vivo measurements. Raman imaging revealed distinct compositional patterns in healthy and degenerated tissues, including GAG depletion and cartilage thinning in degenerated condylar cartilage. Conclusions: Raman-derived biomarkers are strongly associated with TMJ cartilage and disc mechanical properties and outperform Outerbridge grading in explaining variation in condylar indentation modulus. Arthroscopic Raman spectroscopy is technically feasible and may complement visual assessment by providing objective compositional information to support future development of tissue-informed surgical decision-making.

pathology↗