본 연구에서는 PARP1 의 억제가 암 세포의 성장에 어떤 메커니즘을 통해 세포사를 유도하는지 밝히기 위해 실험을 진행하였고, 진행한 결과에서 PARP1 의 억제는 FOXO3 발현을 증가시킴으로써 암을 억제한다는 것을 확인 할 수 있었다. Olaparib 은 PARP1 저해제로써, 암세포를 복구하지 않고 세포사를 유도함으로써 암세포의 성장을 억제하는 효과를 보였다. 이러한 PARP1 억제는 FOXO3 의 활성화를 통해 위암 세포의 성장을 억제 할 수 있음을 보여 주었다.
임상 데이터에서 PARP1 발현과 FOXO3 발현의 손실은 위암의 진행과 관련이 있음을 보여 주었다. 또한, PARP1 의 발현은 좋지 못한 생존 기간을 나타냈고, FOXO3 의 발현이 위암 환자에게 높은 생존 기간을 나타냈다.
결론적으로, 위암의 유리한 독립적인 예후 지표로 PARP1 의 저해에 의한 FOXO3 의 발현을 보여 주었다. PARP1- FOXO3 신호는 임상적인 의미와 암세포의 성장에 중요한 역할을 한다는 것을 입증하였고, 이는 암 치료에 있어 PARP1-FOXO3 신호는 새로운 메커니즘과 임상 통찰력을 제안 할 수 있다.
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- ABSTRACT -
Tumor suppressive effect of PARP1-FOXO3 pathway
Yu-na Jo
Department of Biomedical sciences The Graduate School, Ajou University
(Supervised by professor Hyun Goo Woo)
Gastric cancer is one of the leading causes of cancer in the world every year. Finding the number of new tumor suppressor genes and oncogenes associated with cancer may be useful for the development of early diagnosis and targeted treatment. Poly (ADP-ribose) polymerase1 (PARP1) has been reported to be targeted in many cancer types. So far lots of clinical trials with the specific chemical inhibitor to PARP1 have been done and still in progress. However, there still are not sufficient description how PARP1 inhibition can suppress tumor development. Thus, demonstrated PARP1 inhibition by Olaparib (AZD2281) as well as PARP1 siRNA can attenuate the growth in gastric cancer cells. In addition, the anti-tumor effect of PARP1 inhibition was through the up-regulation of FOXO3 expression.
Also, observed concurrent expression of apoptosis proteins with FOXO3, suggesting that PARP1 inhibition induce apoptosis of cancer cells through FOXO3 activation. Furthermore, clinical implications of PARP1 and FOXO3 expressions were also evaluated using tissue microarrays from 166 tumor stage-matched gastric cancer patients. Multivariate analysis revealed that the expression of PARP1 and loss of the expression of FOXO3 were the independent poor prognostic indicators of overall survival (PARP1; P = 0.021, FOXO3; P = 0.001) and relapse-free survival (PARP1; P = 0.021, FOXO3; P = 0.001). In conclusion, PARP1- FOXO3 signal was proved that an important role in the growth of the clinical significance and cancer, which may PARP1-FOXO3 signal in cancer therapy is to suggest a new mechanism and clinical insight.
Key word: Olaparib, PARP1, FOXO3, Gastric, Carcinoma