Annals of Surgical Oncology

, Volume 16, Issue 9, pp 2638–2644 | Cite as

Comprehensive Analysis of the Clinical Significance of Inducing Pluripotent Stemness-Related Gene Expression in Colorectal Cancer Cells

  • Yasumitsu Saiki
  • Shinya Ishimaru
  • Koshi Mimori
  • Yasushi Takatsuno
  • Makoto Nagahara
  • Hideshi Ishii
  • Kazutaka Yamada
  • Masaki Mori
Translational Research and Biomarkers

Abstract

Background

We previously determined that cancer stem-like cells may influence the susceptibility of colorectal cancer (CRC) cells to chemotherapeutic agents. Although Takahashi and Park identified a set of induced pluripotent stem cell (iPS)-related genes required for normal stem cell maintenance, the precise role of iPS-related gene expression in CRC pathogenesis remains to be determined. The purpose of this study was to clarify the clinical relevance of “stemness”-regulating gene expression in CRC cases.

Materials and methods

Cancer cells were excised from tissues of 79 CRC cases by laser microdissection (LMD), and quantitative RT-PCR was used to evaluate expression levels of the iPS-related genes c-MYC, SOX2, OCT3/4, LIN28, KLF4, and NANOG, and to identify any associations between their expression and clinicopathological CRC progression.

Results

We found that LIN28 expression is significantly associated with lymph node metastasis (p = 0.018) and Dukes stage (p = 0.0319). SOX2expression is also correlated with lymph node metastasis. Furthermore, the ten cases with Dukes D disease expressed significantly higher levels of SOX2transcript than the other 69 cases (p = 0.0136). In contrast, KLF4 expression was inversely related to Dukes stage. Expression of c-MYC, OCT3/4, and NANOG did not appear to have clinical relevance in CRC cases.

Conclusion

The present analysis strongly suggests that altered expression of several iPS-related genes plays a role in CRC pathogenesis.

References

  1. 1.
    Grothey A, Sargent DJ. FOLFOX for stage II colon cancer? A commentary on the recent FDA approval of oxaliplatin for adjuvant therapy of stage III colon cancer. J Clin Oncol. 2005;23:3311–3.PubMedCrossRefGoogle Scholar
  2. 2.
    Marshall J. The role of bevacizumab as first-line therapy for colon cancer. Semin Oncol. 2005;32:S43–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Haraguchi N, Utsunomiya T, Inoue H, et al. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells Dayton, Ohio. 2006;24:506–13.CrossRefGoogle Scholar
  4. 4.
    Ieta K, Tanaka F, Haraguchi N, et al. Biological and genetic characteristics of tumor-initiating cells in colon cancer. Ann Surg Oncol. 2008;15:638–48.PubMedCrossRefGoogle Scholar
  5. 5.
    Park IH, Zhao R, West JA, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008;451:141–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.PubMedCrossRefGoogle Scholar
  7. 7.
    Takahashi K, Yamanaka S Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen Y, Shi L, Zhang L, et al. The molecular mechanism governing the oncogenic potential of sox2 in breast cancer. J Biol Chem. 2008;283:17969–78.PubMedCrossRefGoogle Scholar
  9. 9.
    Ezeh UI, Turek PJ, Reijo RA, Clark AT. Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer. 2005;104:2255–65.PubMedCrossRefGoogle Scholar
  10. 10.
    Looijenga LH, Stoop H, de Leeuw HP, et al. POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 2003;63:2244–50.PubMedGoogle Scholar
  11. 11.
    Ohnishi S, Ohnami S, Laub F, et al. Downregulation and growth inhibitory effect of epithelial-type Kruppel-like transcription factor KLF4, but not KLF5, in bladder cancer. Biochem Biophys Res Commun. 2003;308:251–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Phi JH, Park SH, Kim SK, et al. Sox2 expression in brain tumors: a reflection of the neuroglial differentiation pathway. Am J Surg Pathol. 2008;32:103–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Wang P, Branch DR, Bali M, Schultz GA, Goss PE, Jin T The POU homeodomain protein OCT3 as a potential transcriptional activator for fibroblast growth factor-4 (FGF-4) in human breast cancer cells. Biochem J. 2003;375:199–205.PubMedCrossRefGoogle Scholar
  14. 14.
    Okita K, Ichisaka T, Yamanaka S Generation of germline-competent induced pluripotent stem cells. Nature. 2007;448:313–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Rody A, Karn T, Ruckhaeberle E, et al. Differentially expressed genes of reprogrammed human pluripotent stem cells in breast cancer. Eur J Cancer. 2008;44:1789–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Mimori K, Kataoka A, Yoshinaga K, et al. Identification of molecular markers for metastasis-related genes in primary breast cancer cells. Clin Exp Met. 2005;22:59–67.CrossRefGoogle Scholar
  17. 17.
    Mori M, Mimori K, Yoshikawa Y, et al. Analysis of the gene-expression profile regarding the progression of human gastric carcinoma. Surgery. 2002;131:S39–47.PubMedCrossRefGoogle Scholar
  18. 18.
    Viswanathan SR, Daley GQ, Gregory RI. Selective blockade of microRNA processing by Lin28. Science. 2008;320:97–100.PubMedCrossRefGoogle Scholar
  19. 19.
    Park ET, Gum JR, Kakar S, Kwon SW, Deng G, Kim YS. Aberrant expression of SOX2 upregulates MUC5AC gastric foveolar mucin in mucinous cancers of the colorectum and related lesions. Int J Cancer. 2008;122:1253–60.PubMedCrossRefGoogle Scholar
  20. 20.
    Xu J, Lu B, Xu F, et al. Dynamic down-regulation of Kruppel-like factor 4 in colorectal adenoma-carcinoma sequence. J Cancer Res Clin Oncol. 2008;134:891–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Richards M, Tan SP, Tan JH, Chan WK, Bongso A. The transcriptome profile of human embryonic stem cells as defined by SAGE. Stem Cells (Dayton, Ohio). 2004;22:51–64.PubMedCrossRefGoogle Scholar
  22. 22.
    Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Dangi-Garimella S, Yun J, Eves EM, et al. Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J. 2009;28:347–58.PubMedCrossRefGoogle Scholar
  24. 24.
    Bussing I, Slack FJ, Grosshans H. let-7 microRNAs in development, stem cells and cancer. Trends Mol Med. 2008;14:400–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Katz JP, Perreault N, Goldstein BG, et al. Loss of Klf4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach. Gastroenterology. 2005;128:935–45.PubMedCrossRefGoogle Scholar
  26. 26.
    Wei D, Kanai M, Huang S, Xie K Emerging role of KLF4 in human gastrointestinal cancer. Carcinogenesis. 2006;27:23–31.PubMedCrossRefGoogle Scholar
  27. 27.
    Choi BJ, Cho YG, Song JW, et al. Altered expression of the KLF4 in colorectal cancers. Pathol Res Pract. 2006;202:585–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Pandya AY, Talley LI, Frost AR, et al. Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer. Clin Cancer Res. 2004;10:2709–19.PubMedCrossRefGoogle Scholar
  29. 29.
    Rowland BD, Peeper DS. KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer. 2006;6:11–23.PubMedCrossRefGoogle Scholar
  30. 30.
    Mori M, Barnard GF, Staniunas RJ, Jessup JM, Steele GD, Jr., Chen LB. Prothymosin-alpha mRNA expression correlates with that of c-myc in human colon cancer. Oncogene. 1993;8:2821–6.PubMedGoogle Scholar
  31. 31.
    Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003–7.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2009

Authors and Affiliations

  • Yasumitsu Saiki
    • 1
    • 2
    • 3
  • Shinya Ishimaru
    • 2
    • 3
  • Koshi Mimori
    • 2
    • 3
  • Yasushi Takatsuno
    • 2
    • 3
  • Makoto Nagahara
    • 2
    • 3
  • Hideshi Ishii
    • 2
    • 3
  • Kazutaka Yamada
    • 1
  • Masaki Mori
    • 3
  1. 1.Department of SurgeryTakano HospitalKumamotoJapan
  2. 2.Department of Surgery, Takano HospitalKyushu UniversityBeppuJapan
  3. 3.Department of Surgical Oncology, Medical Institute of BioregulationKyushu UniversityBeppuJapan

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