SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7

Abstract

The therapeutic strategies for advanced gastric cancer (GC) remain unsatisfying and limited. Therefore, it is still imperative to fully elucidate the mechanisms underlying GC metastasis. Here, we report a novel role of SRY-box transcription factor 18 (SOX18), a member of the SOX family, in promoting GC metastasis. The elevated expression of SOX18 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in human GC. SOX18 expression was an independent and significant risk factor for the recurrence and survival in GC patients. Up-regulation of SOX18 promoted GC invasion and metastasis, whereas down-regulation of SOX18 decreased GC invasion and metastasis. Melanoma cell adhesion molecule (MCAM) and C-C motif chemokine ligand 7 (CCL7) are direct transcriptional targets of SOX18. Knockdown of MCAM and CCL7 significantly decreased SOX18-mediated GC invasion and metastasis, while the stable overexpression of MCAM and CCL7 reversed the decrease in cell invasion and metastasis that was induced by the inhibition of SOX18. A mechanistic investigation indicated that the upregulation of SOX18 that was mediated by the CCL7-CCR1 pathway relied on the ERK/ELK1 pathway. SOX18 knockdown significantly reduced CCL7-enhanced GC invasion and metastasis. Furthermore, BX471, a specific CCR1 inhibitor, significantly reduced the SOX18-mediated GC invasion and metastasis. In human GC tissues, SOX18 expression was positively correlated with CCL7 and MCAM expression, and patients with positive coexpression of SOX18/CCL7 or SOX18/MCAM had the worst prognosis. In conclusion, we defined a CCL7-CCR1-SOX18 positive feedback loop that played a pivotal role in GC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of GC.

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Fig. 1: Overexpression of SOX18 indicates poor prognosis in human GC and promotes GC invasion and metastasis.
Fig. 2: SOX18 promotes GC metastasis through upregulating CCL7 and MCAM expression.
Fig. 3: The expression of SOX18 is positively correlated with CCL7 and MCAM expression in human GC.
Fig. 4: Chemokine (C-C motif) ligand 7 (CCL7) induces SOX18 expression via CCR1/ERK/ELK1 pathway.
Fig. 5: SOX18 is essential for CCL7 mediated GC metastasis.
Fig. 6: The CCR1 inhibitor BX471, suppresses SOX18-mediated GC invasion and metastasis.

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Acknowledgements

Research was supported by grants from the National Key Research and Development Program of China 2018YFC1312103 (L.X.), National Natural Science Foundation of China No. 81972237 (L.X.), and No. 81772623 (L.X.).

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Correspondence to Limin Xia.

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Chen, J., Dang, Y., Feng, W. et al. SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7. Oncogene 39, 5536–5552 (2020). https://doi.org/10.1038/s41388-020-1378-1

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