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
-
- Middle Aged
- Signal Transduction*/drug effects
- Humans
- Aged
- Female
- Male
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Zebrafish
- Animals
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Tumor Suppressor Proteins/genetics
- Tumor Suppressor Proteins/metabolism
- Hippo Signaling Pathway*
- Nausea*/chemically induced
- Nausea*/genetics
- Nausea*/prevention & control
- Vomiting*/chemically induced
- Oxaliplatin/adverse effects
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- Capecitabine/administration & dosage
- Capecitabine/adverse effects
- Thrombocytopenia*/chemically induced
- Thrombocytopenia*/genetics
- PubMed
- 39529470 Full text @ Br. J. Pharmacol.
Citation
Li, M., Wang, R., Yan, T., Tao, X., Gao, S., Wang, Z., Chai, Y., Qiu, S., Chen, W. (2024) Dual effects of DLG5 (disks large homolog 5 gene) modulation on chemotherapy-induced thrombocytopenia and nausea/vomiting via the hippo signalling pathway. British journal of pharmacology. 182(4):1090-1106.
Abstract
Background and purpose 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).
Experimental approach 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.
Key results 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.
Conclusion and implications 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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping