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Increased expression of dual-specificity phosphatase 7 in gastric cancer is associated with poor prognosis and chemoresistance
Background
Dual specificity phosphatases (DUSPs) are pivotal regulators of protein activation through dephosphorylating key molecules such as mitogen activated protein kinases, thereby co-ordinating signal transduction and biological processes. DUSP7 specifically dephosphorylates extracellular signal regulated kinases (ERK) 1 and 2 (pertinent for cellular growth) whilst being associated to the induction of inflammatory and apoptotic pathways involving p38-α and JNKs. Unlike other members of the DUSP family, DUSP7’s physiological function remains largely elusive with further exploration required of its involvement in healthy and cancerous tissue. Gastric cancer (GC) is the fourth most common and fatal disease worldwide with approximately 19.3 million new diagnoses made each year. At present, management of chemotherapy, radiotherapy, immunotherapy, and molecularly targeted therapy have proven to be effective treatment in isolation or in combinations of one another; yet the high risk of disease reoccurrence remains. To date, involvement of DUSP7 in GC remains unknown, our present study aims to evaluate the expression of DUSP7 in GC and the clinical implication it may have.
Methods
DUSP7 transcripts were determined in two cohorts of GC tissue samples using real time PCR. One cohort contained 214 gastric tumours and 131 adjacent non-tumour GC tissues with the second comprising of 87 GC and 84 paired adjacent normal GC tissues. The latter cohort received neoadjuvant chemotherapy (NAC). Both cohorts of tissue samples were collected at Peking University Cancer Hospital with informed consent from patients. All protocol and procedures were reviewed and approved by the Peking University Cancer Hospital Ethics Committee. Non-parametric statistical methods were employed for the statistical analyses including One-way ANOVA for comparison of multiple groups and Wilcoxon rank test for matched paired samples. Kaplan-Meier test was used for the survival analysis.
Results
Increased transcript levels of DUSP7 were exhibited in gastric tumours tissues in comparison with paired adjacent non-tumours shown by Wilcoxon rank test in both cohorts. An association between increasing DUSP7 transcript levels and TNM staging of disease progression was found (p= 0.00081) in earlier stages (Stage I and II) compared with advanced stages (Stage III and IV). Further evidence of the positive correlation between DUSP7 and metastasis is found with high expression in advanced tumours from patients who had developed distant metastases in comparison with patients with no distant metastasis (p=0.0009). The increased DUSP7 expression in GC is associated with poor response to the NAC shown by Mann Whitney Test (p=0.0263). Moreover, the overall survival (OS) of patients with DUSP7 high expression tumours were much shorter with a median OS of 18.9 months, p=0.023 compared with 49.3 months of patients with tumours had lower expression of DUSP7.
Conclusions
Collectively, the increase in DUSP7 is associated with poorer patient survival and chemoresistance to the NAC. This warrants further investigation to shed light on the cellular and molecular mechanism of its role in GC and its therapeutic potential.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
