Induction and down-regulation of Sox17 and its possible roles during the course of gastrointestinal tumorigenesis.
OBJECTIVE
The activation of Wnt/beta-catenin signaling causes the development of gastric and colon cancers. Sox17 represses Wnt/beta-catenin signaling and is down-regulated in colon cancer. This study was designed to elucidate the role of Sox17 during the course of gastrointestinal tumorigenesis.


METHODS
Sox17 expression was examined in gastrointestinal tumors of mouse models and humans. The roles of Sox17 in gastric tumorigenesis were examined by cell culture experiments and by construction of Sox17 transgenic mice.


RESULTS
Sox17 was induced in K19-Wnt1/C2mE mouse gastric tumors and K19-Wnt1 preneoplastic lesions, where Wnt/beta-catenin signaling was activated. Consistently, Wnt activation induced Sox17 expression in gastric cancer cells. In contrast, Sox17 was rarely detected by immunohistochemistry in gastric and colon cancers, whereas strong nuclear staining of Sox17 was found in >70% of benign gastric and intestinal tumors. Treatment with a demethylating agent induced Sox17 expression in gastric cancer cells, thus indicating the down-regulation of Sox17 by methylation. Moreover, transfection of Sox17 in gastric cancer cells suppressed both the Wnt activity and colony formation efficiency. Finally, transgenic expression of Sox17 suppressed dysplastic tumor development in K19-Wnt1/C2mE mouse stomach.


CONCLUSIONS
Sox17 plays a tumor suppressor role through suppression of Wnt signaling. However, Sox17 is induced by Wnt activation in the early stage of gastrointestinal tumorigenesis, and Sox17 is down-regulated by methylation during malignant progression. It is therefore conceivable that Sox17 protects benign tumors from malignant progression at an early stage of tumorigenesis, and down-regulation of Sox17 contributes to malignant progression through promotion of Wnt activity.
Du
Yu-Chen
YC
Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Oshima
Hiroko
H
Oguma
Keisuke
K
Kitamura
Takanori
T
Itadani
Hiraku
H
Fujimura
Takashi
T
Piao
Ying-Shi
YS
Yoshimoto
Tanihiro
T
Minamoto
Toshinari
T
Kotani
Hidehito
H
Taketo
Makoto M
MM
Oshima
Masanobu
M
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D053539:Keratin-19 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D000071876:Prostaglandin-E Synthases; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051155:Wnt1 Protein / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
D024002:HMGB Proteins; D053539:Keratin-19; C109188:SOX17 protein, human; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; D051155:Wnt1 Protein; D051176:beta Catenin; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases