G3BP1 interacts with YWHAZ to regulate chemoresistance and predict adjuvant chemotherapy benefit in gastric cancer.
14-3-3 Proteins
/ metabolism
Animals
Biomarkers, Tumor
/ metabolism
Chemotherapy, Adjuvant
DNA Helicases
/ metabolism
Drug Resistance, Neoplasm
/ physiology
Heterografts
Humans
Mice
Poly-ADP-Ribose Binding Proteins
/ metabolism
RNA Helicases
/ metabolism
RNA Recognition Motif Proteins
/ metabolism
Stomach Neoplasms
/ drug therapy
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
30
11
2019
accepted:
26
08
2020
revised:
06
08
2020
pubmed:
30
9
2020
medline:
16
4
2021
entrez:
29
9
2020
Statut:
ppublish
Résumé
A large proportion of gastric cancer patients are susceptible to chemoresistance, while the underlying mechanism remains obscure. Stress granules (SGs) play a self-defence role for tumour cells in inhibiting chemotherapy-induced apoptosis. As an SG assembly effector, G3BP1 (Ras-GTPase-activating protein SH3 domain-binding protein) has been reported to be overexpressed in gastric cancer; thus, here we aim to explore its potent roles in gastric cancer chemoresistance. Kaplan-Meier analysis was used to compare survival rates in gastric cancer patients with different G3BP1 expression. The influence of G3BP1 on gastric cancer cell chemoresistance and apoptosis were evaluated by in vitro and in vivo approaches. The interaction between G3BP1 and YWHAZ was assessed by immunohistochemistry, immunoprecipitation and immunofluorescence. G3BP1 was associated with the poor outcome of gastric cancer patients who received adjuvant chemotherapy. G3BP1 knockdown significantly increased the sensitivity of gastric cancer cells to chemotherapy drugs. Mechanically, cell apoptosis and pro-apoptotic-associated molecules were significantly elevated upon G3BP1 depletion. Gene co-expression network analyses identified YWHAZ as the critical interlayer of G3BP1; as a result, G3BP1 interacted with YWHAZ to sequester Bax into the cytoplasm. Clinically, G3BP1 The expression of G3BP1 and YWHAZ could predict the adjuvant chemotherapy benefit in gastric cancer patients.
Sections du résumé
BACKGROUND
A large proportion of gastric cancer patients are susceptible to chemoresistance, while the underlying mechanism remains obscure. Stress granules (SGs) play a self-defence role for tumour cells in inhibiting chemotherapy-induced apoptosis. As an SG assembly effector, G3BP1 (Ras-GTPase-activating protein SH3 domain-binding protein) has been reported to be overexpressed in gastric cancer; thus, here we aim to explore its potent roles in gastric cancer chemoresistance.
METHODS
Kaplan-Meier analysis was used to compare survival rates in gastric cancer patients with different G3BP1 expression. The influence of G3BP1 on gastric cancer cell chemoresistance and apoptosis were evaluated by in vitro and in vivo approaches. The interaction between G3BP1 and YWHAZ was assessed by immunohistochemistry, immunoprecipitation and immunofluorescence.
RESULTS
G3BP1 was associated with the poor outcome of gastric cancer patients who received adjuvant chemotherapy. G3BP1 knockdown significantly increased the sensitivity of gastric cancer cells to chemotherapy drugs. Mechanically, cell apoptosis and pro-apoptotic-associated molecules were significantly elevated upon G3BP1 depletion. Gene co-expression network analyses identified YWHAZ as the critical interlayer of G3BP1; as a result, G3BP1 interacted with YWHAZ to sequester Bax into the cytoplasm. Clinically, G3BP1
CONCLUSIONS
The expression of G3BP1 and YWHAZ could predict the adjuvant chemotherapy benefit in gastric cancer patients.
Identifiants
pubmed: 32989225
doi: 10.1038/s41416-020-01067-1
pii: 10.1038/s41416-020-01067-1
pmc: PMC7852868
doi:
Substances chimiques
14-3-3 Proteins
0
Biomarkers, Tumor
0
Poly-ADP-Ribose Binding Proteins
0
RNA Recognition Motif Proteins
0
YWHAZ protein, human
0
DNA Helicases
EC 3.6.4.-
G3BP1 protein, human
EC 3.6.4.12
RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
425-436Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 31670806
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81972228
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81872346
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