SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7
Authors: Yijun Wang
Dean Tian
Limin Xia
Kaichun Wu
Yongzhan Nie
Weibo Feng
Danfei Liu
Daiming Fan
Chenyang Qiao
Yunzhi Dang
Jie Chen
Tongyue Zhang
Journal: Oncogene (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Gastric cancer; SOX18; metastasis; AJCC stage; prognosis
Affiliations: Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China., 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 Province, China., Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China. ., 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 Province, China. .

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. 

Retracted: No

PubPeer comments:
 In figure 5F, a micrograph of a mouse has been duplicated and presented as something else. ![file] , 
 #1 Dear Dr. Tanganyikensis, Thank you for your concern. In the original version of this manuscript, we accidentally duplicated the image belonging to MKN28NM-CCL7-LV-shcontrol group when preparing the manuscript in Adobe illustrator. We sincerely apologize for this mistake and the amended version of Fig.5F. is provided below. This change does not affect the results or conclusions reported in the manuscript. We have already contacted the journal for correction. Thank you for your interest in our work! Sincerely, Xia Limin , 
 #1 Dear Dr. Tanganyikensis, Thank you for your concern. In the original version of this manuscript, we accidentally duplicated the image belonging to MKN28NM-CCL7-LV-shcontrol group when preparing the manuscript in Adobe illustrator. We sincerely apologize for this mistake and the amended version of Fig.5F. is provided below. This change does not affect the results or conclusions reported in the manuscript. We have already contacted the journal for correction. Thank you for your interest in our work! Sincerely, Xia Limin ,