Abstract
Poly (ADP-ribose) polymerase1 (PARP1) has been reported as a possible target for chemotherapy in many cancer types. However, its action mechanisms and clinical implications for gastric cancer survival are not yet fully understood. Here, we investigated the effect of PARP1 inhibition in the growth of gastric cancer cells. PARP1 inhibition by Olaparib or PARP1 siRNA could significantly attenuate growth and colony formation of gastric cancer cells, and which were mediated through induction of G2/M cell cycle arrest but not apoptosis. FOXO3A expression was induced by PARP1 inhibition, suggesting that FOXO3A might be one of downstream target of the PARP1 effect on gastric cancer cell growth. In addition, by performing tissue microarrays on the 166 cases of gastric cancer patients, we could observe that the expression status of PARP1 and FOXO3A were significantly associated with overall survival (OS) and relapse-free survival (RFS). Strikingly, combined expression status of PARP1 and FOXO3A showed better prediction for patient's clinical outcomes. The patient group with PARP1+/FOXO3A- expression had the worst prognosis while the patient group with PARP1-/FOXO3A+ had the most favorable prognosis (OS: P = 6.0 × 10(-9), RFS: P = 2.2 × 10(-8)). In conclusion, we suggest that PARP1 and FOXO3A play critical roles in gastric cancer progression, and might have therapeutic and/or diagnostic potential in clinic.
Highlights
Gastric cancer is one of the most common malignancies with heterogeneous clinical outcome [1], but its mechanisms leading to development and/or progression of tumors remain unclear
We suggest that Poly (ADP-ribose) polymerase1 (PARP1) inhibition by Olaparib can suppress the growth of human gastric cancer cells
By performing combined analysis of experimental and clinical data, we could demonstrate that PARP1 and FOXO3A are functionally linked and their expression levels are useful in predicting clinical outcomes of gastric cancer patients
Summary
Gastric cancer is one of the most common malignancies with heterogeneous clinical outcome [1], but its mechanisms leading to development and/or progression of tumors remain unclear. PARP1 is thought of as one of therapeutic targets for the development of anti-cancer treatments for BRCA-mutated tumors, and a variety of clinical trials are actively in progress [5,6,7,8,9,10,11]. PARP1 inhibition has been addressed to attenuate the AKT-associated phosphorylation of forkhead box O (FOXO) transcription factors [17, 18]. Of these FOXO transcription factors, FOXO3A has been known as a downstream target of serine/threonine protein kinase B (PKB)/AKT. To our knowledge, the functional and clinical roles of PARP1 in gastric cancer were not evaluated vigorously yet
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