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.