Role of ROR2 in promoting gastric cancer metastasis by enhancing c-JUN-mediated MMP3 transcription.

Background: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a transmembrane receptor that has a complex role in cancer, acting either to promote or inhibit tumor progression in different tumor types. The effect of ROR2 on gastric cancer is unclear. Methods: Immunohistochemistry was used to investigate the role of ROR2 in the prognosis of gastric cancer. Transwell assay and a BALB/c nude mice pulmonary metastasis model were used to ascertain the role of ROR2 in promoting metastasis in vitro and in vivo. A protein expression array, chromatin immunoprecipitation (ChIP) assay, and luciferase reporter assay were employed to search for the target genes of ROR2. Results: ROR2 was found to be upregulated in gastric cancer tissues, which was correlated with poor disease-free survival (DFS) and overall survival (OS) in gastric cancer patients. Moreover, ROR2 promoted gastric cancer cell migratory and invasive behaviors in vitro and metastasis in vivo. Further research showed that ROR2 promoted gastric cancer metastasis via upregulation of matrix metalloproteinase 3 (MMP3). Analyses of clinical data indicated that high expression of ROR2 was correlated with a high expression of MMP3. Further study showed that ROR2 activated c-JUN by translocating phosphorylated JNK1/2 into the nucleus, and c-JUN interacted directly with the MMP3 promoter, leading to enhanced MMP3 transcription. Conclusions: We report for the first time that ROR2 is upregulated in gastric cancer, promotes metastasis, and is associated with poor prognosis in gastric cancer. The findings suggest that ROR2 may be a promising prognostic predictor for gastric cancer. Silencing the JNK1/2-c-JUN pathway, thereby inhibiting MMP3 expression, may serve as a promising strategy to inhibit gastric cancer progression.