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IGFBP-5 overexpression as a poor prognostic factor in patients with urothelial carcinomas of upper urinary tracts and urinary bladder
  1. Peir-In Liang1,2,3,
  2. Yu-Hui Wang4,
  3. Ting-Feng Wu5,
  4. Wen-Ren Wu6,
  5. Alex C Liao7,
  6. Kun-Hung Shen7,
  7. Chung-Hsi Hsing8,9,
  8. Yow-Ling Shiue6,
  9. Hsuan-Ying Huang10,
  10. Han-Ping Hsu11,
  11. Li-Tzon Chen12,13,14,15,16,
  12. Ching-Yih Lin17,18,
  13. Chein Tai5,
  14. Jui-Yu Wu9,
  15. Chien-Feng Li2,3,5,19
  1. 1Department of Pathology, Chi-Mei Foundation Medical Center, Liouying, Tainan, Taiwan
  2. 2Departments of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan
  3. 3Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
  4. 4Institute of Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan
  5. 5Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan
  6. 6Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan
  7. 7Departments of Urology, Chi-Mei Foundation Medical Center, Tainan, Taiwan
  8. 8Departments of Anesthesiology, Chi-Mei Foundation Medical Center, Tainan, Taiwan
  9. 9College of Medicine, Taipei Medical University, Taipei, Taiwan
  10. 10Departments of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
  11. 11College of Medicine, China Medical University, Taichung, Taiwan
  12. 12National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
  13. 13Departments of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan
  14. 14Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
  15. 15Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
  16. 16Cancer center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
  17. 17Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi-Mei Foundation Medical Center, Tainan, Taiwan
  18. 18Department of Leisure, Recreation, and Tourism Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan
  19. 19Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
  1. Correspondence to Dr Chien-Feng Li, Department of Pathology, Chi-Mei Medical Center, No. 901, Chunghwa Road, Yongkang Dist, Tainan City 710, Taiwan; angelo.p{at}yahoo.com.tw

Abstract

Background Urothelial carcinoma (UC) is prevalent worldwide. Dysregulation of cell growth is a critical event of tumorigenesis and has not been assessed systemically in UC. We thus assessed the published transcriptome of urinary bladder urothelial carcinoma (UBUC) and identified insulin-like growth factor-binding protein-5 (IGFBP-5) as the most significantly upregulated gene associated with the regulation of cell growth. Moreover, validated by using public domain data set, IGFBP-5 expression also significantly predicted worse outcome. IGFBP-5 is one of the binding proteins that regulate insulin-like growth factors (IGFs) and its significance has not been comprehensively evaluated in UCs.

Methods Using immunohistochemistry, we evaluated the IGFBP-5 expression status and its associations with clinicopathological features and survival in 340 cases of upper urinary tract urothelial carcinoma (UTUC) and 295 cases of UBUC. Western blot analysis was used to evaluate IGFBP-5 protein expression in human urothelial cell (HUC) lines.

Results IGFBP-5 overexpression was significantly associated with advanced pT stage (p<0.001), high histological grade (UTUC, p<0.001; UBUC, p=0.035), lymph node metastasis (UTUC, p=0.006; UBUC, p=0.004), vascular invasion (UTUC, p<0.001; UBUC, p=0.003), perineural invasion (UTUC, p=0.034; UBUC, p=0.021) and frequent mitosis (UTUC, p<0.001; UBUC, p=0.023). IGFBP-5 overexpression also independently predicted poor disease-specific survival and metastasis-free survival in both groups of patients. Western blot analysis showed IGFBP-5 protein as overexpressed in human urothelial cancer cell lines and not in normal urothelial cancer cells.

Conclusions IGFBP-5 plays an important role in tumour progression in UC. Its overexpression is associated with advanced tumour stage and conferred poorer clinical outcome.

  • Urinary tract tumours
  • Immunohistochemistry
  • IGF & IGT binding proteins

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