PUBLICATION

Dual effects of DLG5 (disks large homolog 5 gene) modulation on chemotherapy-induced thrombocytopenia and nausea/vomiting via the hippo signalling pathway

Authors
Li, M., Wang, R., Yan, T., Tao, X., Gao, S., Wang, Z., Chai, Y., Qiu, S., Chen, W.
ID
ZDB-PUB-241114-28
Date
2024
Source
British journal of pharmacology   182(4): 1090-1106 (Journal)
Registered Authors
Keywords
DLG5, chemotherapy‐induced nausea and vomiting, hippo signalling pathway, megakaryocyte, thrombocytopenia
MeSH Terms
  • Animals
  • Middle Aged
  • Oxaliplatin/adverse effects
  • Antineoplastic Combined Chemotherapy Protocols/adverse effects
  • Antineoplastic Combined Chemotherapy Protocols/pharmacology
  • Capecitabine/administration & dosage
  • Capecitabine/adverse effects
  • Female
  • Nausea*/chemically induced
  • Nausea*/genetics
  • Nausea*/prevention & control
  • Aged
  • Thrombocytopenia*/chemically induced
  • Thrombocytopenia*/genetics
  • Hippo Signaling Pathway*
  • Humans
  • Male
  • Tumor Suppressor Proteins/genetics
  • Tumor Suppressor Proteins/metabolism
  • Signal Transduction*/drug effects
  • Vomiting*/chemically induced
  • Protein Serine-Threonine Kinases/genetics
  • Protein Serine-Threonine Kinases/metabolism
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism
  • Zebrafish
PubMed
39529470 Full text @ Br. J. Pharmacol.
Abstract
The CAPEOX (combination of oxaliplatin and capecitabine) chemotherapy protocol is widely used for colorectal cancer treatment, but it can lead to chemotherapy-induced adverse effects (CRAEs).
To uncover the mechanisms and potential biomarkers for CRAE susceptibility, we performed whole-genome sequencing on normal colorectal tissue (CRT) before adjuvant chemotherapy. This is followed by in vivo and in vitro verifications for selected gene and CRAE pair.
Our analysis revealed specific germline mutations linked to Grade 2 (or higher) chemotherapy-induced thrombocytopenia (CIT) and nausea/vomiting (CINV). Notably, both CRAEs were associated with mutations in the DLG5 gene. We found that DLG5 mutations related to CIT were associated with increased gene expression, while those associated with CINV were linked to suppressed gene expression, as indicated by the Genotype-Tissue Expression (GTEX) database. In megakaryocytes, overexpression of human DLG5 suppressed the hippo signalling pathway and induced YAP expression. In zebrafish, overexpression of human DLG5 not only reduced platelet production but also inhibited thrombus formation. Subsequent qPCR analysis revealed that DLG5 overexpression affected genes involved in cytoskeleton formation and alpha-granule formation, which could impact the normal generation of proplatelets.
We identified a series of germline mutations associated with susceptibility to CIT and CINV. Of particular interest, we demonstrated that induced and suppressed DLG5 expression is respectively related to CIT and CINV. These findings shed light on the involvement of the hippo signalling pathway and DLG5 in the development of CRAEs, providing valuable insights into potential targets for therapeutic interventions.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping