Smad ubiquitin regulatory factor 1 (SMURF1), a well-known E3 ubiquitin ligase, targets substrate proteins for ubiquitination and proteasomal degradation. Accumulating studies have shown that SMURF1 acts as an oncogenic factor in human malignancies. However, the clinical significance of SMURF1 and its role in gastric cancer (GC) remain unclear. The expression of SMURF1 was detected in 68 cases of GC and corresponding tumor-adjacent specimens. Our results revealed that SMURF1 was prominently overexpressed in GC specimens compared to corresponding tumor-adjacent tissues. Furthermore, increased levels of SMURF1 mRNA were also observed in GC cell lines. Clinicopathological detection ascertained that SMURF1-positive expression was associated with large tumor size, more lymph nodes and distant metastasis as well as advanced tumor-node-metastasis (TNM) stage of GC. Notably, GC patients with SMURF1 positive-expressing tumors exhibited a significant decreased survival. Further experiments illustrated that SMURF1 knockdown significantly inhibited proliferation, migration and invasion of MGC-803 cells, while SMURF1 overexpression prominently promoted these behaviors in SGC-7901 cells. In vivo studies revealed that SMURF1 knockdown markedly inhibited tumor growth and liver metastasis of GC. Mechanically, SMURF1 inversely regulated the expression of DOC-2/DAB2 interactive protein (DAB2IP) in GC tissues and cells. Furthermore, DAB2IP restoration revealed similar effects to SMURF1 knockdown on MGC-803 cells with decreased proliferation, migration and invasion. In addition, the PI3K/Akt pathway and its downstream targets including c-Myc and ZEB1 were potentially involved in the oncogenic role of the SMURF1/DABIP axis. Collectively, the present study revealed the first evidence that SMURF1 can be potentially used as a clinical biomarker and target for novel treatment of human GC.
[1]Jilin Univ, Dept Gastrointestinal Colorectal & Anal Surg, China Japan Union Hosp, 126 Xiantai St, Changchun 130033, Jilin, Peoples R China.
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