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Published in: Virchows Archiv 3/2012

01-03-2012 | Original Article

SOX9 expression and its methylation status in gastric cancer

Authors: Minhua Sun, Hiroshi Uozaki, Rumi Hino, Akiko Kunita, Aya Shinozaki, Tetsuo Ushiku, Takashi Hibiya, Kimiko Takeshita, Maya Isogai, Kenzo Takada, Masashi Fukayama

Published in: Virchows Archiv | Issue 3/2012

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Abstract

SOX9 is a member of the SOX [Sry-related high-mobility group (HMG) box] family and is required for the development and differentiation of multiple cell lineages. To clarify the significance of SOX9 in gastric carcinoma (GC), immunohistochemical expression of SOX9 and the CpG island methylation status of SOX9 were evaluated and compared with clinicopathological factors including overall survival. SOX9 expression was immunohistochemically evaluated in 382 GC tumors and the methylation status was examined in 121 GC tumors. SOX9 expression and its methylation status in six GC cell lines, their Epstein–Barr virus (EBV)-infected cell lines, and two EBV-associated GC cell lines was also examined. The SOX9 expression increased from non-neoplastic mucosa to early cancer. High expression of SOX9 was seen in 212 cases (56%). SOX9 expression was inversely related to advanced tumor stage, vessel infiltration, nodal metastasis, and EBV infection. Fifty-eight (48%) of 121 GC tumors had a methylated promoter in GC and the methylated status was related to low expression. The expression and methylation status were not related to prognosis. Three of six cell lines had increased methylation through EBV infection and decreased SOX9 expression. Upregulation of SOX9 is related to GC development. Downregulation by promoter methylation is related to GC progression and EBV infection. SOX9 is closely related to GC carcinogenesis and EBV-associated GC carcinogenesis.
Literature
1.
go back to reference Uozaki H, Fukayama M (2008) Epstein–Barr virus and gastric carcinoma—viral carcinogenesis through epigenetic mechanisms. Int J Clin Exp Pathol 1:198–216PubMed Uozaki H, Fukayama M (2008) Epstein–Barr virus and gastric carcinoma—viral carcinogenesis through epigenetic mechanisms. Int J Clin Exp Pathol 1:198–216PubMed
2.
go back to reference Uozaki H, Barua RR, Sun M et al (2011) Transcriptional factor typing with SOX2, HNF4aP1, and CDX2 closely relates to tumor invasion and Epstein–Barr virus status in gastric cancer. Int J Clin Exp Pathol 4:230–240PubMed Uozaki H, Barua RR, Sun M et al (2011) Transcriptional factor typing with SOX2, HNF4aP1, and CDX2 closely relates to tumor invasion and Epstein–Barr virus status in gastric cancer. Int J Clin Exp Pathol 4:230–240PubMed
3.
go back to reference Park DY, Srivastava A, Kim GH et al (2010) CDX2 expression in the intestinal-type gastric epithelial neoplasia: frequency and significance. Mod Pathol 23:54–61CrossRef Park DY, Srivastava A, Kim GH et al (2010) CDX2 expression in the intestinal-type gastric epithelial neoplasia: frequency and significance. Mod Pathol 23:54–61CrossRef
4.
go back to reference Haveri H, Westerholm-Ormio M, Lindfors K et al (2008) Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa. BMC Gastroenterol 8:9PubMedCrossRef Haveri H, Westerholm-Ormio M, Lindfors K et al (2008) Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa. BMC Gastroenterol 8:9PubMedCrossRef
5.
go back to reference Lefebvre V, Dumitriu B, Penzo-Mendez A et al (2007) Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. Int J Biochem Cell Biol 39:2195–2214PubMedCrossRef Lefebvre V, Dumitriu B, Penzo-Mendez A et al (2007) Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. Int J Biochem Cell Biol 39:2195–2214PubMedCrossRef
6.
go back to reference Kent J, Wheatley SC, Andrews JE et al (1996) A male-specific role for SOX9 in vertebrate sex determination. Development 122:2813–2822PubMed Kent J, Wheatley SC, Andrews JE et al (1996) A male-specific role for SOX9 in vertebrate sex determination. Development 122:2813–2822PubMed
7.
go back to reference Lefebvre V, Huang W, Harley VR et al (1997) SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Mol Cell Biol 17:2336–2346PubMed Lefebvre V, Huang W, Harley VR et al (1997) SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Mol Cell Biol 17:2336–2346PubMed
8.
go back to reference Stolt CC, Lommes P, Sock E et al (2003) The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev 17:1677–1689PubMedCrossRef Stolt CC, Lommes P, Sock E et al (2003) The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev 17:1677–1689PubMedCrossRef
9.
go back to reference Perez-Alcala S, Nieto MA, Barbas JA (2004) LSox5 regulates RhoB expression in the neural tube and promotes generation of the neural crest. Development 131:4455–4465PubMedCrossRef Perez-Alcala S, Nieto MA, Barbas JA (2004) LSox5 regulates RhoB expression in the neural tube and promotes generation of the neural crest. Development 131:4455–4465PubMedCrossRef
10.
go back to reference Foster JW, Dominguez-Steglich MA, Guioli S et al (1994) Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372:525–530PubMedCrossRef Foster JW, Dominguez-Steglich MA, Guioli S et al (1994) Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372:525–530PubMedCrossRef
11.
go back to reference De Santa BP, Bonneaud N, Boizet B et al (1998) Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene. Mol Cell Biol 18:6653–6665 De Santa BP, Bonneaud N, Boizet B et al (1998) Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene. Mol Cell Biol 18:6653–6665
12.
go back to reference Blache P, van de Wetering M, Duluc I et al (2004) SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol 166:37–47PubMedCrossRef Blache P, van de Wetering M, Duluc I et al (2004) SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol 166:37–47PubMedCrossRef
13.
go back to reference Fukayama M, Hino R, Uozaki H (2008) Epstein–Barr virus and gastric carcinoma: virus–host interactions leading to carcinoma. Cancer Sci 99:1726–1733PubMedCrossRef Fukayama M, Hino R, Uozaki H (2008) Epstein–Barr virus and gastric carcinoma: virus–host interactions leading to carcinoma. Cancer Sci 99:1726–1733PubMedCrossRef
14.
go back to reference Lu B, Fang Y, Xu J et al (2008) Analysis of SOX9 expression in colorectal cancer. Am J Clin Pathol 130:897–904PubMedCrossRef Lu B, Fang Y, Xu J et al (2008) Analysis of SOX9 expression in colorectal cancer. Am J Clin Pathol 130:897–904PubMedCrossRef
15.
go back to reference Thomsen MK, Ambroisine L, Wynn S et al (2010) SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation. Cancer Res 70:979–987PubMedCrossRef Thomsen MK, Ambroisine L, Wynn S et al (2010) SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation. Cancer Res 70:979–987PubMedCrossRef
16.
go back to reference Japanese Gastric Cancer Association (1998) Japanese classification of gastric carcinoma—2nd English edition. Gastric Cancer 1:10–24PubMedCrossRef Japanese Gastric Cancer Association (1998) Japanese classification of gastric carcinoma—2nd English edition. Gastric Cancer 1:10–24PubMedCrossRef
17.
go back to reference Lauren P (1965) The two histological main types of gastric carcinoma. Diffuse and so-called intestinal type carcinoma. An attempt at histoclinical classification. Acta Pathol Microbiol Scand 64:31–49PubMed Lauren P (1965) The two histological main types of gastric carcinoma. Diffuse and so-called intestinal type carcinoma. An attempt at histoclinical classification. Acta Pathol Microbiol Scand 64:31–49PubMed
18.
go back to reference Sinicrope FA, Ruan SB, Cleary KR et al (1995) bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res 55:237–241PubMed Sinicrope FA, Ruan SB, Cleary KR et al (1995) bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res 55:237–241PubMed
19.
go back to reference Iwasaki Y, Chong JM, Hayashi Y et al (1998) Establishment and characterization of a human Epstein–Barr virus-associated gastric carcinoma in SCID mice. J Virol 72:8321–8326PubMed Iwasaki Y, Chong JM, Hayashi Y et al (1998) Establishment and characterization of a human Epstein–Barr virus-associated gastric carcinoma in SCID mice. J Virol 72:8321–8326PubMed
20.
go back to reference Imai S, Nishikawa J, Takada K (1998) Cell-to-cell contact as an efficient mode of Epstein–Barr virus infection of diverse human epithelial cells. J Virol 72:4371–4378PubMed Imai S, Nishikawa J, Takada K (1998) Cell-to-cell contact as an efficient mode of Epstein–Barr virus infection of diverse human epithelial cells. J Virol 72:4371–4378PubMed
21.
go back to reference Shimizu N, Yoshiyama H, Takada K (1996) Clonal propagation of Epstein–Barr virus (EBV) recombinants in EBV-negative Akata cells. J Virol 70:7260–7263PubMed Shimizu N, Yoshiyama H, Takada K (1996) Clonal propagation of Epstein–Barr virus (EBV) recombinants in EBV-negative Akata cells. J Virol 70:7260–7263PubMed
22.
go back to reference Aleman A, Adrien L, Lopez-Serra L et al (2008) Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays. Br J Cancer 98:466–473PubMedCrossRef Aleman A, Adrien L, Lopez-Serra L et al (2008) Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays. Br J Cancer 98:466–473PubMedCrossRef
23.
go back to reference Chang MS, Uozaki H, Chong JM et al (2006) CpG island methylation status in gastric carcinoma with and without infection of Epstein–Barr virus. Clin Cancer Res 12:2995–3002PubMedCrossRef Chang MS, Uozaki H, Chong JM et al (2006) CpG island methylation status in gastric carcinoma with and without infection of Epstein–Barr virus. Clin Cancer Res 12:2995–3002PubMedCrossRef
24.
go back to reference Stolt CC, Wegner M (2010) SoxE function in vertebrate nervous system development. Int J Biochem Cell Biol 42:437–440PubMedCrossRef Stolt CC, Wegner M (2010) SoxE function in vertebrate nervous system development. Int J Biochem Cell Biol 42:437–440PubMedCrossRef
25.
go back to reference Akiyama H (2008) Control of chondrogenesis by the transcription factor Sox9. Mod Rheumatol 18:213–219PubMedCrossRef Akiyama H (2008) Control of chondrogenesis by the transcription factor Sox9. Mod Rheumatol 18:213–219PubMedCrossRef
26.
go back to reference Thomsen MK, Francis JC, Swain A (2008) The role of Sox9 in prostate development. Differentiation 76:728–735PubMedCrossRef Thomsen MK, Francis JC, Swain A (2008) The role of Sox9 in prostate development. Differentiation 76:728–735PubMedCrossRef
27.
go back to reference Barrionuevo F, Scherer G (2010) SOX E genes: SOX9 and SOX8 in mammalian testis development. Int J Biochem Cell Biol 42:433–436PubMedCrossRef Barrionuevo F, Scherer G (2010) SOX E genes: SOX9 and SOX8 in mammalian testis development. Int J Biochem Cell Biol 42:433–436PubMedCrossRef
28.
go back to reference Moniot B, Biau S, Faure S et al (2004) SOX9 specifies the pyloric sphincter epithelium through mesenchymal-epithelial signals. Development 131:3795–3804PubMedCrossRef Moniot B, Biau S, Faure S et al (2004) SOX9 specifies the pyloric sphincter epithelium through mesenchymal-epithelial signals. Development 131:3795–3804PubMedCrossRef
29.
go back to reference Mori-Akiyama Y, van den Born M, van Es JH et al (2007) SOX9 is required for the differentiation of paneth cells in the intestinal epithelium. Gastroenterology 133:539–546PubMedCrossRef Mori-Akiyama Y, van den Born M, van Es JH et al (2007) SOX9 is required for the differentiation of paneth cells in the intestinal epithelium. Gastroenterology 133:539–546PubMedCrossRef
30.
go back to reference Bastide P, Darido C, Pannequin J et al (2007) Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J Cell Biol 178:635–648PubMedCrossRef Bastide P, Darido C, Pannequin J et al (2007) Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J Cell Biol 178:635–648PubMedCrossRef
31.
go back to reference Yasui W, Oue N, Sentani K et al (2009) Transcriptome dissection of gastric cancer: identification of novel diagnostic and therapeutic targets from pathology specimens. Pathol Int 59:121–136PubMedCrossRef Yasui W, Oue N, Sentani K et al (2009) Transcriptome dissection of gastric cancer: identification of novel diagnostic and therapeutic targets from pathology specimens. Pathol Int 59:121–136PubMedCrossRef
32.
go back to reference Chen Y, Zhang Y-Z, Zhou Z-G et al (2006) Identification of differently expressed genes in human colorectal adenocarcinoma. World J Gastroenterol 12:1025–1032PubMed Chen Y, Zhang Y-Z, Zhou Z-G et al (2006) Identification of differently expressed genes in human colorectal adenocarcinoma. World J Gastroenterol 12:1025–1032PubMed
33.
go back to reference Jiang SS, Fang W-T, Hou Y-H et al (2010) Upregulation of SOX9 in lung adenocarcinoma and its involvement in the regulation of cell growth and tumorigenicity. Clin Cancer Res 16:4363–4373PubMedCrossRef Jiang SS, Fang W-T, Hou Y-H et al (2010) Upregulation of SOX9 in lung adenocarcinoma and its involvement in the regulation of cell growth and tumorigenicity. Clin Cancer Res 16:4363–4373PubMedCrossRef
34.
go back to reference Wang H, Leav I, Ibaragi S et al (2008) SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion. Cancer Res 68:1625–1630PubMedCrossRef Wang H, Leav I, Ibaragi S et al (2008) SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion. Cancer Res 68:1625–1630PubMedCrossRef
35.
go back to reference Passeron T, Valencia JC, Namiki T et al (2009) Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid. J Clin Invest 119:954–963PubMed Passeron T, Valencia JC, Namiki T et al (2009) Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid. J Clin Invest 119:954–963PubMed
36.
go back to reference Chakravarty G, Moroz K, Makridakis NM et al (2011) Prognostic significance of cytoplasmic SOX9 in invasive ductal carcinoma and metastatic breast cancer. Exp Biol Med (Maywood) 236:145–155CrossRef Chakravarty G, Moroz K, Makridakis NM et al (2011) Prognostic significance of cytoplasmic SOX9 in invasive ductal carcinoma and metastatic breast cancer. Exp Biol Med (Maywood) 236:145–155CrossRef
37.
38.
go back to reference Vidal VP, Ortonne N, Schedl A (2008) SOX9 expression is a general marker of basal cell carcinoma and adnexal-related neoplasms. J Cutan Pathol 35:373–379PubMedCrossRef Vidal VP, Ortonne N, Schedl A (2008) SOX9 expression is a general marker of basal cell carcinoma and adnexal-related neoplasms. J Cutan Pathol 35:373–379PubMedCrossRef
39.
go back to reference Ramocki NM, Wilkins HR, Magness ST et al (2008) Insulin receptor substrate-1 deficiency promotes apoptosis in the putative intestinal crypt stem cell region, limits Apcmin/+ tumors, and regulates Sox9. Endocrinology 149:261–267PubMedCrossRef Ramocki NM, Wilkins HR, Magness ST et al (2008) Insulin receptor substrate-1 deficiency promotes apoptosis in the putative intestinal crypt stem cell region, limits Apcmin/+ tumors, and regulates Sox9. Endocrinology 149:261–267PubMedCrossRef
40.
Metadata
Title
SOX9 expression and its methylation status in gastric cancer
Authors
Minhua Sun
Hiroshi Uozaki
Rumi Hino
Akiko Kunita
Aya Shinozaki
Tetsuo Ushiku
Takashi Hibiya
Kimiko Takeshita
Maya Isogai
Kenzo Takada
Masashi Fukayama
Publication date
01-03-2012
Publisher
Springer-Verlag
Published in
Virchows Archiv / Issue 3/2012
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-012-1201-7

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