Tumor suppressive effect of PARP1 and FOXO3A in gastric cancers and its clinical implications

// See-Hyoung Park 1, 2, * , Kyu Yun Jang 4, * , Min Jae Kim 1, 3, * , Sarah Yoon 1 , Yuna Jo 1, 3 , So Mee Kwon 1, 3 , Kyoung Min Kim 4 , Keun Sang Kwon 5 , Chan Young Kim 6 , Hyun Goo Woo 1, 3 1 Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea 2 Program in Nano Science and Technology, Department of Transdisciplinary Studies, Seoul National University Graduate School of Convergence Science and Technology, Suwon, Republic of Korea 3 Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, Republic of Korea 4 Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea 5 Department of Preventive Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea 6 Department of Surgery, Chonbuk National University Medical School, Jeonju, Republic of Korea * These authors have contributed equally to this work Correspondence to: Hyun Goo Woo, e-mail: hg@ajou.ac.kr Keywords: olaparib, PARP1, FOXO3A, prognosis, G2/M arrest Received: May 27, 2015      Accepted: October 22, 2015       Published: November 02, 2015 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.