2. Elevated Beclin 1 expression is correlated with HIF-1α in predicting poor prognosis of nasopharyngeal carcinoma Xiang-Bo Wan, Xin-Juan Fan, Ming-Yuan Chen, Jin Xiang, Pei-Yu Huang, Ling Guo, Xiang-Yuan Wu, Jie Xu, Zi-Jie Long, Yan Zhao, Wei-Hua Zhou, Hai-Qiang Mai, Quentin Liu and Ming-Huang Hong Autophagy 6:3, 395-404; April 1, 2010 指導教授：鄭伯智老師 林宏榮老師 報告者：李依陵 學號： N99H0009 報告日期： 2011.5.22

3. Outline Introduction Materials and methods Results Discussion Conclusion

4. Introduction

5. Autophagy Also known as type 2 nonapoptotic cell death,is characterized by the delivery of cytosolic material and organelles to lysosomes for bulk degradation. The functions as a stress responser, upregulated by nutrient starvation, hypoxia, or other therapeutic stress reactions, and generally protects against cell death, facilitating adaptive survival.

10. Nasopharyngeal carcinoma (NPC), an Epstein- Barr virus (EBV)-related head and neck cancer with the highest occurrence in Southeast Asia. Klionsky DJ.,2007;Kroemer G,Jaattela M,2005. Radiotherapy displays favorable therapeutic outcomes for early stage patients, local failure and distant metastasis are still the major issues for the poor survival of advanced patients. Morselli E et. Al,2009.

11. The prognostic markers, including epidermal growth factor receptor (EGFR), CENP-H, PIK3CA, hnRNP K, EBV DNA, 14-3-3σ and annexin I, the risk lassification of patient outcome was defined more accurately. Overexpression of EGFR, for example, occurred in 90% of head and neck squamous cell arcinoma(HNSCC), 10 including NPC, and predicted an inferior patient outcome.

12. The autophagic effects of the Beclin 1 protein may be attributed to its interaction with several important cellular molecules, including HIF-1, mTOR, Bcl-2,Bcl-xL, JNK, Ambra1, Bif-1, Vps34, Atg14 and UVRAG. The previous survival analysis confirms that Beclin 1 is a novel prognostic biomarker in predicting the post-treatment outcome for several solid tumors, such as breast, ovarian, brain, liver, gastric and colorectal cancers.

13. Its dual function as a novel molecular target for cancer therapy and promising prognostic indicator for disease monitoring. The detected a close relationship between HIF-1α and Beclin 1 Expression, elevated Beclin 1 expression predicted an inferior OS in the HIF- 1α-positive expression subset of patients.

14. AIM To identify more novel molecular markers that not only can predict the prognosis individually but also provide promising therapy targets will be of great benefit for advanced NPC patients.

15. Patients and materials

16. Patients Use a randomized controlled trial; the patients are nonkeratinizing or undifferentiated carcinoma of nasopharynx, without radiotherapy, chemotherapy and oncological surgery history, aged 18–65 years; a series of detailed clinical examination, and treatment planning 。

17. Materials and methods Semi-quantitative assessment of immunohistochemical staining. Western blot analysis. The ROC curve analysis. Clinical outcome assessment. Statistical analysis ： (1) 卡方檢定 (2) 費雪 檢定 (3) 存活分析.

18. Results

19. 32;47.8%

21. 5.63 5.65 5.66 5.63

22. 測試祖

23. 總體祖

24. 測試祖 36 例 訓練組 34 例

26. 訓練組測試組

27. Discussion

28. Beclin 1 expression, which was an independent prognostic marker for OS, PFS and DMFS in testing set and overall atients. The first identified mammalian autophagy effector, Beclin 1 acts as an obligatory allosteric activator of the class III PtdIns3K in production of PtdIns(3)P

29. Discussion Beclin 1 had been suggested as a therapeutic molecular target. In mda-7/IL-24 leukemia models, for example, inhibition of autophagy by the PtdIns3K inhibitor wortmannin results in reduced Beclin 1 expression and is associated with significantly enhanced cell death.

30. Discussion That Beclin 1 was positively correlated with HIF-1α expression (p< 0.05). Combined with previous studies, that HIF-1α- associated Beclin 1 high expression may favor the NPC cells surviving from chemoradiotherapy and metastasizing to distant organs, suggesting a potential molecular target for NPC therapy.

31. Conclusion The study demonstrated that Beclin 1 was an independent prognostic biomarker of overall survival and distant metastasis-free survival for advanced NPC. HIF-1α-associated Beclin 1 high expression might be a novel therapeutic molecular target for NPC.

32. Thank you For your attention!!