Evaluating the Expression of Oct4 as a Prognostic Tumor Marker in Bladder Cancer

Document Type: Original Article

Authors

1 Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

2 Department of Pathology, Labbafi-Nejad Medical Centre, Shahid Beheshti University of Medical Sciences, Tehran, Iran

3 Urology and Nephrology Research Centre, Labbafi-Nejad Medical Centre, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

Objective(s)
The key transcriptional regulator Oct4 is one of the self-renewal and differentiation-related factors in cancer stem cells, where it maintains "stemness" state. Cancer stem cells have been identified in a variety of solid malignancies. They are a small population of tumor cells with stem cell characteristics, which are a likely cause of relapse in cancer patients. Due to high incidence, mortality, and recurrence rates of bladder cancer and the necessity of accurate prediction of malignant behavior of the tumors, we evaluated the prognostic value of Oct4 expression in formalin-fixed paraffin-embedded (FFPE) tissues of bladder cancer.
Materials and Methods
In this study, Oct4 expression was evaluated in 52 (FFPE) tissues of bladder cancer. RNA extraction from samples of 30 patients from the archive of Labbafi-Nejad Medical Centre in Tehran was performed and Oct4 expression levels were examined by semi-quantitative RT-PCR. The intracellular distribution of Oct4 protein was also determined by immunohistochemistry (IHC).
Results
The results revealed a significant correlation between the expression level of Oct4 and the tumors’ grade and stage. A mostly cytoplasmic distribution of Oct4 protein was also confirmed by IHC.
Conclusion
All together, our data indicate that the expression level of Oct4 gene is correlated with the clinical and histopathological prognostic indexes of tumors and thus can be considered as a potential prognostic tumor marker.

Keywords


1. Denzinger S, Mohren K, Knuechel R, Wild PJ, Burger M, Wieland WF, et al. Improved clonality analysis of multifocal bladder tumors by combination of histopathologic organ mapping, loss of heterozygosity, fluorescence in situ hybridization and p53 analyses. Hum Pathol 2006; 37:143–151.

2. Junker K, Wolf M, Schubert J. Molecular clonal analysis of recurrent bladder cancer. Oncol Rep 2005; 14:319–323.

3. Gil J, Stembalska A, Pesz KA, Sasiadek MM. Cancer stem cells: the theory and perspectives in cancer therapy. J App Genet 2008; 49:193–199.

4. Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 2004; 23:7274–7282.

5. Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 2004; 51: 1–28.

6. Webster JD, Yuzbasiyan-Gurkan V, Trosko JE, Chang CC, Kiupel M. Expression of the embryonic transcription factor Oct4 in canine neoplasms: A potential marker for stem cell subpopulations in neoplasia. Vet Pathol 2007; 44:893–900.

7. Lengner CJ, Camargo FD, Hochedlinger K, Welstead GG, Zaidi S, Gokhale S, et al. Oct4 expression is not required for mouse somatic stem cell self-renewal. Cell Stem Cell 2007; 1:403–415.

8. Okumura-Nakanishi S, Saito M, Niwa H, Ishikawa F. Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. J Biol Chem 2005; 280:5307–5317.

9. Sun Y, Li H, Yang H, Rao M, Zhan M. Mechanisms controlling embryonic stem cell self-renewal and differentiation. Crit Rev Eukaryot Gene Expr 2006; 16:211–231.

10. Atlasi Y, Mowla SJ, Ziaee SAM, Bahrami AR. Oct4, an embryonic stem cell marker, is highly expressed in bladder cancer. Int J Cancer 2007; 120:1598-1602.

11. Card DA, Hebbar PB, Li L, Trotter KW, Komatsu Y, Mishina Y, et al. Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells. Mol Cel Biol 2008; 28:6426–6438.

12. Campbell PA, Perez-Iratxeta C, Andrade-Navarro MA, Rudnicki MA. Oct4 targets regulatory nodes to modulate stem cell function. PLoS ONE 2007; 2:e553.

13. Van den Berg D, Snoek T, Mullin NP, Yates A, Bezstarosti K, Demmers J, et al. An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell 2010; 6:369–381.

14. Pardo M, Lang B, Yu L, Prosser H, Bradley A, Babu MM, et al. An expanded Oct4 interaction network: implications for stem cell biology, development, and disease. Cell Stem Cell 2010; 6:382–395.

15. Asadi MH, Mowla SJ, Fathi F, Aleyasin SA, Asadzadeh J, Atlasi Y. Oct4B1, a novel spliced variant of Oct4, is highly expressed in gastric cancer and acts as an anti-apoptotic factor. Int J Cancer 2011; 128:2645-2652.

16. Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE. Oct4 expression in adult human stem cells: Evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis 2005; 26:495–502.

17. Atlasi Y, Mowla SJ, Ziaee SAM, Gokhale PJ, Andrews PW. Oct4 spliced variants are differentially expressed in human pluripotent and nonpluripotent cells. Stem Cells 2008; 26: 3068-3074.

18. Xu K, Zhu Z, Zeng F. Expression and significance of Oct4 in bladder cancer. J Huazhong Univ Sci Technolog Med Sci. 2008; 27(6):675-677.

19. Trosko JE, Tai MH. Adult stem cell theory of the multi-stage, multimechanism theory of carcinogenesis: Role of inflammation on the promotion of initiated stem cells. Contrib Microbiol 2006; 13:45- 65.

20. Pan GJ, Chang ZY, Scholer HR, Pei D. Stem cell pluripotency and transcription factor Oct4. Cell Research 2002; 12:321-329.

21. Blast the human Genome.Available at: http://www.ncbi.nlm.nih.gov/genome/seq/hsBlast.html

22. Sambrook J, Russel DW. Molecular cloning a laboratory manual. 3rd ed. New York: Cold Spring Harbor Laboratory Press; 2001.

23. Website of International Agency for Research on Cancer: http://globocan.iarc.fr/

24. Hanke M, Hoefig K, Merz H, Feller AC, Kausch I, Jocham D, et al. A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer, urolonc. 2009; 1: 1-7.

25. Kausch I, Bohle A. Molecular aspects of bladder cancer: III. Prognostic markers of bladder cancer. Eur Urol 2002; 41:15-29.

26. Stein JP, Grossfeld GD, Ginsberg DA, Esrig D, Freeman JA, Figueroa AJ, et al. Prognostic markers in bladder cancer: a contemporary review of the literature. J Urol 1998; 160:645-659.

27. Boiani M, Scholer HR. Regulatory networks in embryo-derived pluripotent stem cells. Nat Rev Mol Cell Biol 2005; 6:872-884.

28. Babaie Y, Herwig R, Greber B, Brink TC, Wruck W, Groth D, et al. Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells. Stem Cells 2007; 25;500-510.

29. Jin T, Branch DR, Zhang X, Qi S, Youngson B, Goss PE. Examination of POU homeobox gene expression in human breast cancer cells. Int J Cancer 1999; 81:104-112.

30. Cheng L, Thomas A, Roth LM, Zheng W, Michael H, Karim FW. Oct4: a novel biomarker for dysgerminoma of the ovary. Am J Surg Pathol 2004; 28:1341-1346.

31. Jones TD, Ulbright TM, Eble JN, Baldridge LA, Cheng L. Oct4 staining in testicular tumors: a sensitive and specific marker for seminoma and embryonal carcinoma. Am J Surg Pathol 2004; 28:935-940.

32. Matthai C, Horvat R, Noe M, Nagele F, Radjabi A, van Trotsenburg M. Oct4 expression in human endometrium. Mol Hum Reprod 2006; 12:7-10.