Gastric cancer (GC) is the second leading cause of death among patients with cancer in China. The primary reason of GC treatment failure is metastasis. Therefore, identifying metastatic biomarkers and clarifying the regulatory mechanisms involved in the GC metastatic process are important. Here, we found that KIAA1199, a cell migration-inducing protein, was significantly overexpressed in GC and correlated with lymph node metastasis and poorer patient survival. Additionally, the introduction of KIAA1199 dramatically promoted GC cell proliferation and migration in vitro and in vivo, and the inhibition of KIAA1199 suppressed GC cell growth and migration and induced GC cell apoptosis. Cell migration is a functional consequence of the epithelial-mesenchymal transition (EMT). In this study, we found that KIAA1199 inhibition or overexpression regulated the expression of E-cadherin and N-cadherin through KIAA1199 binding to WW domain binding protein 11 (WBP11) and protein tyrosine phosphatase type IVA, member 3 (PTP4A3) and through the subsequent activation of the FGFR4/Wnt/β-catenin and EGFR signaling pathways. More importantly, ectopic expression of WBP11 or PTP4A3 blocked the stimulatory effects of KIAA1199 on GC cell proliferation and migration. Meanwhile, we illustrated that KIAA1199 was a target gene of miR-29c-3p and that miR-29c-3p overexpression led to decreased migration of GC cells in vitro and in vivo by suppressing the expression of KIAA1199 and several key proteins in the Wnt/β-catenin and EGFR signaling pathways (e.g., WBP11, FGFR4, and PTP4A3). Taken together, these data demonstrate that KIAA1199 promotes GC metastasis by activating EMT-related signaling pathways and that miR-29c-3p regulates GC cell migration in vitro and in vivo by regulating KIAA1199 expression and activating the FGFR4/Wnt/β-catenin and EGFR signaling pathways. These findings provide a new understanding of GC development and progression and may provide novel therapeutic strategies for GC.
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This work was supported by the Chongqing Youth Science and Technology Talent Training Project (cstc2014kjrc-qnrc10008) and National Science Foundation of China (NSFC) (81872392).
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Wang, L., Yu, T., Li, W. et al. The miR-29c-KIAA1199 axis regulates gastric cancer migration by binding with WBP11 and PTP4A3. Oncogene 38, 3134–3150 (2019). https://doi.org/10.1038/s41388-018-0642-0
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