S100A16 is a Prognostic Marker for Lung Adenocarcinomas

  • Saito, Keita (Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University) ;
  • Kobayashi, Makoto (Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University) ;
  • Nagashio, Ryo (Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University) ;
  • Ryuge, Shinichiro (Department of Respiratory Medicine, Kitasato University) ;
  • Katono, Ken (Department of Respiratory Medicine, Kitasato University) ;
  • Nakashima, Hiroyasu (Department of Thoracic and Cardiovascular Surgery, Kitasato University) ;
  • Tsuchiya, Benio (Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University) ;
  • Jiang, Shi-Xu (Department of Pathology, School of Medicine, Kitasato University) ;
  • Saegusa, Makoto (Department of Pathology, School of Medicine, Kitasato University) ;
  • Satoh, Yukitoshi (Department of Thoracic and Cardiovascular Surgery, Kitasato University) ;
  • Masuda, Noriyuki (Department of Respiratory Medicine, Kitasato University) ;
  • Sato, Yuichi (Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University)
  • Published : 2015.11.04


Background: Many functional molecules controlling diverse cellular function are included in low-molecular weight proteins and peptides. Materials and Methods: To identify proteins controlling function in lung adenocarcinomas (AC), we performed two-dimensional gel electrophoresis employing tricine-SDS polyacrylamide in the second dimension (tricine 2-DE). This system was able to detect proteins under 1 kDa even with post-translational modifications. To confirm the utility of detected proteins as novel tumor markers for AC, we performed immunohistochemical analysis using 170 formalin-fixed and paraffin-embedded lung AC tissues. Results: Tricine 2-DE revealed that five proteins including S100A16 were overexpressed in lung AC-derived cells compared with lung squamous cell carcinoma, small cell carcinoma, and large cell neuroendocrine carcinoma-derived cells. Immunohistochemically, S100A16 showed various subcellular localization in lung cancer tissues and a membranous staining status was correlated with the T-factor (P=0.0008), pathological stage (P=0.0015), differentiation extent (P=0.0001), lymphatic invasion (P=0.0007), vascular invasion (P=0.0001), pleural invasion (P=0.0087), and gender (P=0.039), but not with the age or smoking history. More importantly, membranous staining of S100A16 was significantly correlated with a poorer overall survival of either stage I (P=0.0088) or stage II / III (P=0.0003) lung AC patients, and multivariate analysis confirmed that membranous expression of S100A16 was an independent adverse prognostic indicator (P=0.0001). Conclusions: The present results suggest that S100A16 protein is a novel prognostic marker for lung AC.


  1. Chen H, Xu C, Jin Q, et al (2014). S100 protein family in human cancer. Am J Cancer Res, 4, 89-115.
  2. Diamandis EP (2006). Peptidomics for cancer diagnosis: present and future. J Proteome Res, 5, 2079-82.
  3. Dong Q, Yan X, Kilpatrick LE, et al (2014). Tandem mass spectral libraries of peptides in digests of individual proteins: Human Serum Albumin (HSA). Mol Cell Proteomics, 13, 2435-49.
  4. Goldstraw P, Crowley J, Chansky K, et al (2007). The IASLC lung cancer staging project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol, 2, 706-14.
  5. Gross SR, Sin CG, Barraclough R, et al (2014). Joining S100 proteins and migration: for better or for worse, in sickness and in health. Cell Mol Life Sci, 71, 1551-79.
  6. He K, Wen XY, Li AL, et al (2013). Serum peptidome variations in a healthy population: reference to identify cancer-specific peptides. PLoS One, 8, 63724.
  7. Hernandez JL, Padilla L, Dakhel S, et al (2013). Therapeutic targeting of tumor growth and angiogenesis with a novel anti-S100A4 monoclonal antibody. PLoS One, 8, 72480.
  8. Jiang SX, Kameya T, Asamura H, et al (2004). hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors. Mod Pathol, 17, 222-9.
  9. Jin Q, Chen H, Luo A, et al (2011). S100A14 stimulates cell proliferation and induces cell apoptosis at different concentrations via receptor for advanced glycation end products (RAGE). PLoS One, 6, 19375.
  10. Kobayashi M, Nagashio R, Ryuge S, et al (2014). Acquisition of useful sero-diagnostic autoantibodies using the same patients’ sera and tumor tissues. Biomed Res, 35, 133-43.
  11. Liu Y, Zhang R, Xin J, et al (2011). Identification of S100A16 as a novel adipogenesis promoting factor in 3T3-L1 cells. Endocrinol, 152, 903-11.
  12. Marenholz I, Heizmann CW (2004). S100A16, a ubiquitously expressed EF-hand protein which is up-regulated in tumors. Biochemical Bioph Res Commun, 313, 237-44.
  13. Nagashio R, Sato Y, Jiang SX, et al (2008). Detection of tumorspecific autoantibodies in sera of patients with lung cancer. Lung Cancer, 62, 364-73.
  14. Sapkota D, Costea DE, Ibrahim SO, et al (2013). S100A14 interacts with S100A16 and regulates its expression in human cancer cells. PLoS One, 8, 76058.
  15. Schmitt T, Ogris C, Sonnhammer EL (2014). FunCoup 3.0: database of genome-wide functional coupling networks. Nucleic Acids Res, 42, 380-8.
  16. Siegel R, Naishadham D, Jemal A (2013). Cancer statistics, 2013. CA Cancer J Clin, 63, 11-30.
  17. Tan HT, Low J, Lim SG, et al (2009). Serum autoantibodies as biomarkers for early cancer detection. FEBS J, 276, 6880-904.
  18. Tanaka M, Ichikawa-Tomikawa N, Shishito N, et al (2015). Co-expression of S100A14 and S100A16 correlates with a poor prognosis in human breast cancer and promotes cancer cell invasion. BMC Cancer, 15, 53.
  19. Travis WD CT, Corrin B, Shimosato EY (1999). World Health Organization Inter-national histological classification of tumors; histological typing of lung and pleural tumors. Springer.
  20. Zhao CB, Bao JM, Lu YJ, et al (2014). Co-expression of RAGE and HMGB1 is associated with cancer progression and poor patient outcome of prostate cancer. Am J Cancer Res, 4, 369-77.
  21. Zhou W, Pan H, Xia T, et al (2014). Up-regulation of S100A16 expression promotes epithelial-mesenchymal transition via Notch1 pathway in breast cancer. J Biomed Sci, 21, 97.

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