Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and invasion and metastasis of gastric cancer represent the major reason for its poor prognosis. In this study, we found that loss of the receptor for activated C-kinase 1 (RACK1) promoted the metastasis of gastric cancer by enhancing the autocrine of interleukin (IL)-8 in vitro and in vivo. MicroRNA array identified that RACK1 modulated the expression of a series of microRNAs including microRNA-302 cluster, and RACK1 modulated the IL-8 expression and tumor invasion through microRNA-302c. Moreover, up-regulation of IL-8 in turn decreased the level of microRNA-302c and induced IL-8 expression in feedback manner. Tissue microarray also indicated that RACK1 was correlated with invasion/metastasis phenotype, IL-8 expression as well as five-year survival in clinical cases of gastric cancer. Together, our results imply that loss of RACK1 in gastric cancer links epigenetics to inflammatory cytokines to promote tumor metastasis.