Transcription factor SOX2 up-regulates stomach-specific pepsinogen A gene expression

  • Yasuyo Tani
  • Yoshimitsu Akiyama
  • Hiroshi Fukamachi
  • Kazuyoshi Yanagihara
  • Yasuhito Yuasa
Original Paper

Abstract

Purpose

Transcription factor SOX2 is expressed in normal gastric mucosae but not in the normal colon. We aimed to clarify the role of SOX2 with reference to pepsinogen expression in the gastrointestinal epithelium.

Methods

We analyzed expression of SOX2 and pepsinogens, differentiation markers of the stomach, in ten gastric cancer (GC) and ten colorectal cancer (CRC) cell lines. The effects of over-expression and down-regulation of SOX2 on pepsinogen expression were also examined.

Results

Six GC and five CRC cell lines showed SOX2 expression on RT-PCR. Expression of pepsinogen A was detectable in eight GC and seven CRC cell lines, whereas the majority of the cell lines expressed pepsinogen C. Over-expression of SOX2 up-regulated expression of pepsinogen A but not that of pepsinogen C in 293T human embryonic kidney cells, and some GC and CRC cell lines. Moreover, pepsinogen A expression was significantly reduced by SOX2 RNA interference in two GC cell lines.

Conclusion

These data suggest that SOX2 plays an important role in regulation of pepsinogen A, and ectopic expression of SOX2 may be associated with abnormal differentiation of colorectal cancer cells.

Keywords

SOX2 Pepsinogen A/C Gastric cancer Colorectal cancer Ectopic expression 

References

  1. Bai YQ, Yamamoto H, Akiyama Y, Tanaka H, Takizawa T, Koike M, Yagi OK, Saitoh K, Takeshita K, Iwai T, Yuasa Y (2002) Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach. Cancer Lett 176:47–55PubMedCrossRefGoogle Scholar
  2. Basque JR, Chenard M, Chailler P, Menard D (2001) Gastric cancer cell lines as models to study human digestive functions. J Cell Biochem 81:241–251PubMedCrossRefGoogle Scholar
  3. Diez-Itza I, Merino AM, Tolivia J, Vizoso F, Sanchez LM, Lopez-Otin C (1993) Expression of pepsinogen C in human breast tumours and correlation with clinicopathologic parameters. Br J Cancer 68:637–640PubMedGoogle Scholar
  4. Ferrari S, Harley VR, Pontiggia A, Goodfellow PN, Lovell-Badge R, Bianchi ME (1992) SRY, like HMG1, recognizes sharp angles in DNA. EMBO J 11:4497–4506PubMedGoogle Scholar
  5. Foltmann B (1981) Gastric proteinases-structure, function, evolution and mechanism of action. Essays Biochem 17:52–84PubMedGoogle Scholar
  6. Gubbay J, Collignon J, Koopman P, Capel B, Economou A, Munsterberg A, Vivian N, Goodfellow P, Lovell-Badge R (1990) A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 346:245–250PubMedCrossRefGoogle Scholar
  7. Higuchi R, Krummel B, Saiki RK (1988) A general method of in vitro preparation and specific mutagenesis of DNA fragments: study of protein and DNA interactions. Nucleic Acids Res 16:7351–7367PubMedCrossRefGoogle Scholar
  8. Ishii Y, Rex M, Scotting PJ, Yasugi S (1998) Region-specific expression of chicken Sox2 in the developing gut and lung epithelium: regulation by epithelial mesenchymal interactions. Dev Dyn 213:464–475PubMedCrossRefGoogle Scholar
  9. Kageyama T (2002) Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development. Cell Mol Life Sci 59:288–306PubMedCrossRefGoogle Scholar
  10. Kamachi Y, Uchikawa M, Kondoh H (2000) Pairing SOX off: with partners in the regulation of embryonic development. Trends Genet 16:182–187PubMedCrossRefGoogle Scholar
  11. Ley C, Mohar A, Guarner J, Herrera-Goepfert R, Figueroa LS, Halperin D, Parsonnet J (2001) Screening markers for chronic atrophic gastritis in Chiapas, Mexico. Cancer Epidemiol Biomarkers Prev 10:107–112PubMedGoogle Scholar
  12. Li XL, Eishi Y, Bai YQ, Sakai H, Akiyama Y, Tani M, Takizawa T, Koike M, Yuasa Y (2004) Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma. Int J Oncol 24:257–263PubMedGoogle Scholar
  13. Merino AM, Vazquez J, Rodriguez JC, Fernandez R, Quintela I, Gonzalez LO, Sanchez LM, Vizoso F (2000) Pepsinogen C expression in tumors of extragastric origin. Int J Biol Markers 15:165–170PubMedGoogle Scholar
  14. Miki K, Ichinose M, Kawamura N, Matsushima M, Ahmad HB, Kimura M, Sano J, Tashiro T, Kakei N, Oka H (1989) The significance of low serum pepsinogen levels to detect stomach cancer associated with extensive chronic gastritis in Japanese subjects. Jpn J Cancer Res 80:111–114PubMedGoogle Scholar
  15. Mizoshita T, Inada K, Tsukamoto T, Nozaki K, Joh T, Itoh M, Yamamura Y, Ushijima T, Nakamura S, Tatematsu M (2004) Expression of the intestine-specific transcription factors, Cdx1 and Cdx2, correlates shift to an intestinal phenotype in gastric cancer cells. J Cancer Res Clin Oncol 130:29–36PubMedCrossRefGoogle Scholar
  16. Ren CY, Akiyama Y, Miyake S, Yuasa Y (2004) Transcription factor GATA-5 selectively up-regulates mucin gene expression. J Cancer Res Clin Oncol 130:245–252PubMedCrossRefGoogle Scholar
  17. Rojo JV, Merino AM, Gonzalez LO, Vizoso F (2002) Expression and clinical significance of pepsinogen C in epithelial ovarian carcinomas. Eur J Obstet Gynecol Reprod Biol 104:58–63PubMedCrossRefGoogle Scholar
  18. Sakai H, Eishi Y, Li XL, Akiyama Y, Miyake S, Takizawa T, Konishi N, Tatematsu M, Koike M, Yuasa Y (2004) PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas. Gut 53:320–330CrossRefGoogle Scholar
  19. Sakamoto N, Fukuda K, Watanuki K, Sakai D, Komano T, Scotting PJ, Yasugi S (2000) Role for cGATA-5 in transcriptional regulation of the embryonic chicken pepsinogen gene by epithelial-mesenchymal interactions in the developing chicken stomach. Dev Biol 223:103–113PubMedCrossRefGoogle Scholar
  20. Samloff IM (1971) Cellular localization of group I pepsinogens in human gastric mucosa by immunofluorescence. Gastroenterology 61:185–188PubMedGoogle Scholar
  21. Samloff IM, Liebman WM (1973) Cellular localization of the group II pepsinogens in human stomach and duodenum by immunofluorescence. Gastroenterology 65:36–42PubMedGoogle Scholar
  22. Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Goodfellow PN (1990) A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346:240–244PubMedCrossRefGoogle Scholar
  23. Smiraglia DJ, Rush LJ, Fruhwald MC, Dai Z, Held WA, Costello JF, Lang JC, Eng C, Li B, Wright FA, Caligiuri MA, Plass C (2001) Excessive CpG island hypermethylation in cancer cell lines versus primary human malignancies. Hum Mol Genet 10:1413–1419PubMedCrossRefGoogle Scholar
  24. Tang J, Wong RN (1987) Evolution in the structure and function of aspartic proteases. J Cell Biochem 33:53–63PubMedCrossRefGoogle Scholar
  25. Wegner M (1999) From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res 27:1409–1420PubMedCrossRefGoogle Scholar
  26. Weiss MA (2001) Floppy SOX: mutual induced fit in hmg (high-mobility group) box-DNA recognition. Mol Endocrinol 15:353–362PubMedCrossRefGoogle Scholar
  27. Wilson M, Koopman P (2002) Matching SOX: partner proteins and co-factors of the SOX family of transcriptional regulators. Curr Opin Genet Dev 12:441–446PubMedCrossRefGoogle Scholar
  28. Wu XS, Akiyama Y, Igari T, Kawamura T, Hiranuma S, Shibata T, Tsuruta K, Koike M, Arii S, Yuasa Y (2005) Expression of homeodomain protein CDX2 in gallbladder carcinomas. J Cancer Res Clin Oncol 131:271–278PubMedCrossRefGoogle Scholar
  29. Yamamoto Y, Bai YQ, Yuasa Y (2003) Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression. Biochem Biophys Res Commun 300:813–818PubMedCrossRefGoogle Scholar
  30. Yanagihara K, Tanaka H, Takigahira M, Ino Y, Yamaguchi Y, Toge T, Sugano K, Hirohashi S (2004) Establishment of two cell lines from human gastric scirrhous carcinoma that possess the potential to metastasize spontaneously in nude mice. Cancer Sci 95:575–582PubMedCrossRefGoogle Scholar
  31. Yuan H, Corbi N, Basilico C, Dailey L (1995) Developmental specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev 9:2635–2645PubMedGoogle Scholar
  32. Yuasa Y (2003) Control of gut differentiation and intestinal type gastric carcinogenesis. Nat Rev Cancer 3:592–600PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Yasuyo Tani
    • 1
  • Yoshimitsu Akiyama
    • 1
  • Hiroshi Fukamachi
    • 1
  • Kazuyoshi Yanagihara
    • 2
  • Yasuhito Yuasa
    • 1
  1. 1.Department of Molecular Oncology, Graduate School of Medicine and DentistryTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Central Animal LaboratoryNational Cancer Center Research InstituteTokyoJapan

Personalised recommendations