Expression and Prognostic Implications of FOXO3a and Ki67 in Lung Adenocarcinomas

  • Liu, Hong-Bin (Department of Pathology, The First People's Hospital of Nantong) ;
  • Gao, Xiang-Xiang (Department of Oncology, Nantong University Cancer Hospital) ;
  • Zhang, Qing (Department of Pathology, Affiliated Hospital of Nantong University) ;
  • Liu, Jian (Department of Oncology, Affiliated Hospital of Nantong University) ;
  • Cui, Yuan (Department of Pathology, Affiliated Hospital of Nantong University) ;
  • Zhu, Yan (Department of Pathology, The First People's Hospital of Nantong) ;
  • Liu, Yi-Fei (Department of Pathology, Affiliated Hospital of Nantong University)
  • Published : 2015.03.09


To investigate the significance of FOXO3a and Ki67 in human lung adenocarcinomas. Envision immunohistochemical staining and Western blotting were used to examine the protein expression of FOXO3a in 127 cases of human lung adenocarcinoma specimens. The positive rate in lung adenocarcinoma (55.9%) was lower than that in normal tissues (80%). We found that the expression of FOXO3a was closely related with the degree of differentiation, TNM staging, lymph node metastasis and survival. In addition, significant differences in the different pathological types of lung adenocarcinoma cases (P<0.01). The FOXO3a positive rate of the acini as the main type (APA) (86.7%) and the lepidic as the main type (LPA) (82.4%) was higher than the solid as the main type (SPA) (50.0%), the papilla as the main type (PPA) (42.9%) and the micropapilla as the main type (MPA) (9.4%). Moreover, the expression of FOXO3a was negatively related with Ki67 expression. Our results suggested that the expression of FOXO3a is closely correlated with the aggressiveness of lung adenocarcinoma. It was indicated that disregulation of FOXO3a might play key roles in the occurrence and development of lung a denocarcinoma and joint detection of the two markers might play an important role in diagnosing tumors.


  1. Blake Jr, Mikse OR, Freeman WM, et al (2010). FOXO3a elicits a pro-apoptotic transcription program and cellular response to human lung carcinogen nicotine-derived nitrosaminoketone (NNK). Lung Cancer, 67, 37-47.
  2. Brunet A, Kanai F, Stehn J, et al (2002). 14-3-3 trans its to the nucleus and participates in dynamic nucleocytoplasmic transport.J Cell Biol, 156, 817-28.
  3. Castrillon DH, Miao I, Kollipara R, et al (2003). Suppression of ovarian folic leactivation in mice by the transcription fator FOXO3a. Science, 301, 215-8.
  4. Chen J, Gomes AR, Monteiro LJ, et al (2010). Constitutively nuclear FOXO3a localization predicts poor survival and promotes akt phosphorylation in breast cancer. PLoS One, 5, 12293.
  5. Chiacchiera F, Simone C (2009). Inhibition of p38alpha unveils an AMPK-FoxO3A axis linking autophagy to cancer-specific metabolism. Autophagy, 5, 1030-3.
  6. Dansen TB, Smits LM, Vantriest MH, et al (2009). Redox sensitive cysteines bridge p300/CBP-mediated acetylation and FOXO4 activity. Nat Chem Biol, 5, 664-72.
  7. Drobniene M, Cic6niene A, Zelviene TP, et al (2011). Targeted therapy in patients with non-small cell lung cancer previously treated with chemotherapy. Medicina, 47, 520-5.
  8. Fernandez de Mattos S, Villalonga P, Clardy J et al (2008). FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells. Mol Cancer Ther, 7, 3237-46.
  9. Ge Y F, Sun J, Jin C J, et al (2013). AntagomiR-27a targets FOXO3a in glioblastoma and suppresses U87 cell growth in vitro and in vivo. Asian Pac J Cancer Prev, 14, 963-8.
  10. Habashy HO, Rakha EA, Aleskandarany M, et al (2011). FOXO3a nuclear localization is associated with good prognosis in luminal-like breast cancer. Breast Cancer Res Treat, 129, 11-21.
  11. Huang H, Regan KM, Wang F, et al (2005). Skp2 inhibits FOXO1 in tumor suppression through ubiquit in mediated degradation. Proc Natl Acad Sci USA, 102, 1649-54.
  12. Jin GS, Kondo E, Miyake T, et al (2004). Expression and intracellular localization of FKHRL1 in mammary gland neoplasms. Acta Med Okayama, 58, 197-205.
  13. Karger S, Weidinger C, Krause K, et al (2009). FOXO3a:a novel player in thyroid carcinogenesis? Endocr Relat Cancer, 16, 189-99.
  14. Levanon K, Sapoznik S, Bahar-Shany K, et al (2014). FOXO3a loss is a frequent early event in high-grade pelvic serous carcinogenesis. Oncogene, 33, 4424-32.
  15. Lu M, Ma J, Xue W, et al (2009). The expression and prognosis of FOXO3a and Skp2 in human hepatocellular carcinoma. Pathol OncolRes, 15, 679-87.
  16. Lu M, Xiang J, Xu F, et al (2012). The expression and significance of pThr32-FOXO3a in human ovarian cancer. Medical Oncology, 29, 1258-64.
  17. Lu M, Zhao Y, Xu F, et al (2012). The expression and prognosis of FOXO3a and Skp2 in human ovarian cancer. Medical Oncology, 29, 3409-15.
  18. Nho R S, Hergert P (2014). FoxO3a and disease progression. World J Biol Chem, 5, 346-54.
  19. Paik J H, Kollipara R, Chu G, et al (2007). FOXOs are lineagerestricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell, 128, 309-323.
  20. Potente M, Urbich C, Sasaki K, et al (2005). Involvement of FOXO Transcription factors in angiogenesis and postnatal neovascularization. Clin Invest, 115, 2382-92.
  21. Russell P A, Wainer Z, Wright G M, et al (2011). Does lung adenocarcinoma subtype predict patient survival? A clinicopathologic study based on the new international association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol, 2, 1-9.
  22. SO CW, Cleary ML (2003). Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood, 101, 633-9.
  23. Travis W D, Brambilla E, Noguchi M, et al (2011). International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol, 6, 244-85.
  24. Tsai KL, Sun YJ, Huang CY, et al (2007). Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification. Nucleic Acids Res, 35, 6984-94.
  25. Vogt PK, Jiang H, Aoki M (2005). Triple layer control:phosphorylation, acetylation and ubiquitination of FOXO proteins. Cell Cycle, 4, 908-13.
  26. Wang J X, Zhang Y Y, Yu X M, et al (2012). Role of centromere protein H and Ki67 in relapse-free survival of patients after primary surgery for hypopharyngeal cancer. Asian Pac J Cancer Prev, 13, 821-5.
  27. Yoshizawa A, Motoi N, Riely GJ, et al (2011). Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol, 24, 653-64.
  28. Zou Y, Tsai WB, Cheng CJ, et al (2008). Forkhead box transcription factor FOXO3a suppresses estrogen-dependent breast cancer cell proliferation and tumorigenesis. Breast Cancer Res, 10, 21.

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