SOX9 suppresses colon cancer via inhibiting epithelial-mesenchymal transition and SOX2 induction

Ying Feng; Ningxin Zhu; Karan Bedi; Jinju Li; Chamila Perera; Maranne Green; Naziheh Assarzadegan; Yali Zhai; Qingzhi Liu; Veerabhadran Baladandayuthapani; Jason R. Spence; Kathleen R. Cho; Eric R. Fearon

doi:10.1172/JCI184115

¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Feng, Y. in: JCI | PubMed | Google Scholar

¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Zhu, N. in: JCI | PubMed | Google Scholar

¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Bedi, K. in: JCI | PubMed | Google Scholar |

¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Li, J. in: JCI | PubMed | Google Scholar

¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

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¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

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¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

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¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

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¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

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¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Baladandayuthapani, V. in: JCI | PubMed | Google Scholar

¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

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¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

Find articles by Cho, K. in: JCI | PubMed | Google Scholar |

¹Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States of America

³Department of Pathology, University of Michigan Medical School, Ann Arbor, United States of America

⁴Department of Biostatistics, University of Michigan, Ann Arbor, United States of America

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J Clin Invest. https://doi.org/10.1172/JCI184115.
Copyright © 2025, Feng et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published April 3, 2025 - Version history

The Wnt/β-catenin pathway regulates expression of the SOX9 gene, which encodes SRY-box transcription factor 9, a differentiation factor and potential β-catenin regulator. Because APC tumor suppressor defects in ~80% of colorectal cancers (CRCs) activate the Wnt/β-catenin pathway, we studied SOX9 inactivation in CRC biology. Compared to effects of Apc inactivation in mouse colon tumors, combined Apc and Sox9 inactivation instigated more invasive tumors with epithelial-mesenchymal transition (EMT) and SOX2 stem cell factor upregulation. In an independent mouse CRC model with combined Apc, Kras, and Trp53 defects, Sox9 inactivation promoted SOX2 induction and distant metastases. About 20% of 171 human CRCs showed loss of SOX9 protein expression, which correlated with higher tumor grade. In an independent group of 376 CRC patients, low SOX9 gene expression was linked to poor survival, earlier age at diagnosis, and increased lymph node involvement. SOX9 expression reductions in human CRC were linked to promoter methylation. EMT pathway gene expression changes were prominent in human CRCs with low SOX9 expression and in a mouse cancer model with high SOX2 expression. Our results indicate SOX9 has tumor suppressor function in CRC; its loss may promote progression, invasion, and poor prognosis by enhancing EMT and stem cell phenotypes.

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SOX9 suppresses colon cancer via inhibiting epithelial-mesenchymal transition and SOX2 induction

Ying Feng,¹ Ningxin Zhu,¹ Karan Bedi,² Jinju Li,² Chamila Perera,² Maranne Green,¹ Naziheh Assarzadegan,³ Yali Zhai,³ Qingzhi Liu,² Veerabhadran Baladandayuthapani,⁴ Jason R. Spence,¹ Kathleen R. Cho,³ and Eric R. Fearon¹

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SOX9 suppresses colon cancer via inhibiting epithelial-mesenchymal transition and SOX2 induction

Ying Feng,1 Ningxin Zhu,1 Karan Bedi,2 Jinju Li,2 Chamila Perera,2 Maranne Green,1 Naziheh Assarzadegan,3 Yali Zhai,3 Qingzhi Liu,2 Veerabhadran Baladandayuthapani,4 Jason R. Spence,1 Kathleen R. Cho,3 and Eric R. Fearon1

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Ying Feng,¹ Ningxin Zhu,¹ Karan Bedi,² Jinju Li,² Chamila Perera,² Maranne Green,¹ Naziheh Assarzadegan,³ Yali Zhai,³ Qingzhi Liu,² Veerabhadran Baladandayuthapani,⁴ Jason R. Spence,¹ Kathleen R. Cho,³ and Eric R. Fearon¹