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SOX13 promotes colorectal cancer metastasis by transactivating SNAI2 and c-MET

Oncogene volume 39, pages 3522–3540 (2020)Cite this article

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Abstract

Metastasis is a major cause of high recurrence and poor survival of patients with colorectal cancer (CRC), although the mechanisms associated with this process remain poorly understood. In this study, we report a novel mechanism by which SOX13 promotes CRC metastasis by transactivating SNAI2 and c-MET. SOX13 overexpression was significantly correlated with more aggressive clinicopathological features of CRC and indicated poor prognosis in two independent cohorts of CRC patients (cohort I, n = 363; cohort II, n = 390). Overexpression of SOX13-promoted CRC migration, invasion, and metastasis, whereas SOX13 downregulation caused the opposite effects. Further mechanistic investigation identified SNAI2 and MET as important target genes of SOX13 using serial deletion and site-directed mutagenesis luciferase reporter and chromatin immunoprecipitation (ChIP) assays, as well as functional complementation analyses. In addition, SOX13 was shown to be a direct target of HGF/STAT3 signaling, and the c-MET inhibitor crizotinib blocked the HGF/STAT3/SOX13/c-MET axis, significantly inhibiting SOX13-mediated CRC migration, invasion and metastasis. Moreover, in clinical CRC tissues, SOX13 expression was positively correlated with the expression of SNAI2, c-MET, and HGF. CRC patients with positive coexpression of SOX13/SNAI2, SOX13/c-MET, or HGF/SOX13 exhibited a worse prognosis. In summary, SOX13 is a promising prognostic biomarker in patients with CRC, and blocking the HGF/STAT3/SOX13/c-MET axis with crizotinib could be a new therapeutic strategy to prevent SOX13-mediated CRC metastasis.

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Fig. 1: SOX13 is upregulated in human CRC tissues and indicates poor prognosis.
Fig. 2: SOX13 promotes CRC migration, invasion, and metastasis.
Fig. 3: SNAI2 and MET are direct transcriptional targets of SOX13.
Fig. 4: SOX13 promotes CRC metastasis by upregulating SNAI2 and c-MET expression.
Fig. 5: HGF induces SOX13 expression through the JAK2/STAT3 signaling pathway.
Fig. 6: SOX13 expression is positively correlated with HGF, SNAI2, and c-MET expression in human CRC tissues.
Fig. 7: The c-MET inhibitor crizotinib suppresses SOX13-mediated CRC metastasis.

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Acknowledgements

Research was supported by grants from the National Key Research and Development Program of China 2018YFC1312103 (LX), National Natural Science Foundation of China No. 81972237 (LX), No. 81772623 (LX), No. 81627807 (KW), No.81430072 (DF) and No. 81421003 (KW), National Key Research and Development Program of China SQ2017YFSF090132 (KW), and National Center for Clinical Research of Digestive Diseases 2015BAI13B07 (DF). We also would like to thank Qingling An and Jianhua Dou from the Fourth Military Medical University for providing excellent technical assistance.

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  1. These authors contributed equally: Feng Du, Xiaowei Li, Weibo Feng, Chenyang Qiao

Authors and Affiliations

  1. Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Feng Du, Dean Tian & Limin Xia

  2. State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, 710032, Shaanxi, China

    Feng Du, Weibo Feng, Chenyang Qiao, Jie Chen, Mingzuo Jiang, Meirui Qian, Yongzhan Nie, Daiming Fan, Kaichun Wu & Limin Xia

  3. Department of Gastroenterology, Chinese People Liberation Army 306th Hospital, Beijing, China

    Feng Du

  4. Department of Gastroenterology, Navy General Hospital, Beijing, 100048, China

    Xiaowei Li

  5. Department of General Surgery, Chinese People’s Liberation Army General Hospital, Fuxing Road No. 28, Haidian District, Beijing, 100853, China

    Zhaoyan Qiu

  6. Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Dean Tian & Limin Xia

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Du, F., Li, X., Feng, W. et al. SOX13 promotes colorectal cancer metastasis by transactivating SNAI2 and c-MET. Oncogene 39, 3522–3540 (2020). https://doi.org/10.1038/s41388-020-1233-4

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