Abstract
BACKGROUNDA 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.METHODSKaplan–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.RESULTSG3BP1 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, G3BP1highYWHAZhigh gastric cancer patients displayed the worst outcome compared with other patients after chemotherapy.CONCLUSIONSThe expression of G3BP1 and YWHAZ could predict the adjuvant chemotherapy benefit in gastric cancer patients.
Highlights
A large proportion of gastric cancer patients are susceptible to chemoresistance, while the underlying mechanism remains obscure
High G3BP1 correlates with poor survival of gastric cancer patients who received chemotherapy By analysing microarray datasets from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) database, we found that the mRNA level of G3BP1, but not that of family member G3BP2, was significantly higher in human gastric cancer samples than in normal tissue samples (Supplementary Fig. 1a–e)
The results showed that high G3BP1 expression was significantly associated with poor Overall survival (OS) and progression-free survival of gastric cancer patients in the cohort who received postoperative chemotherapy, but not in the surgery-alone group (Fig. 1e, f)
Summary
A large proportion of gastric cancer patients are susceptible to chemoresistance, while the underlying mechanism remains obscure. The standard clinical treatments are potentially curative surgery with conventional adjuvant or neoadjuvant chemotherapy for resectable advanced gastric cancer,[5,6,7,8] or palliative chemotherapy for unresectable gastric cancer.[9] the large patient cohorts involved in the randomised controlled trials (RCTs) are heterogeneous populations that may lead to difficulties to interpret for every specific subgroup.[10] even in the previous RCTs that demonstrated a survival benefit with chemotherapy, capecitabine and oxaliplatin could only reduce the hazard ratio of 5-year diseasefree survival to 0.58,7 and the overall response rates were only.
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