5-Fluorouracil (5-FU) resistance has been long considered as an obstacle to the efficacy of chemotherapy in colorectal cancer (CRC).In this study,we demonstrated the role of miR-20b-5p-regulated syndecan-2 (SDC2) in 5-FU resistance of CRC cells.5-FU-resistant SW480 CRC cells were established by treatment of SW480 cells with stepwise increase of 5-FU concentration.The results showed that SDC2 was expressed significantly higher in SW480/5-FU cells than in SW480/WT cells as revealed by quantitative real-time polymerase chain reaction and western blot analysis.MTT assay and BrdU assay showed that SDC2 overexpression led to increased cell survival rate,while SDC2 knockdown reversed the drug resistance of SW480/5-FU cells.Wound healing and transwell invasion assays revealed that knockdown of SDC2 inhibited the migratory and invasive ability of SW480/5-FU cells.Moreover,animal experiments indicated that si-SDC2 plays a suppressive role in tumor growth in vivo.We also confirmed that miR-20b-5p interacted with SDC2,which reversed the effect of SDC2 in SW480/5-FU cells via the c-Jun N-terminal kinase (JNK)/extracellular regulated protein kinases (ERK) signaling pathway.These findings showed that JNK/ERK signaling pathway is involved in miR-20b-5p/SDC2 axis-mediated 5-FU resistance in SW480/5-FU cells,indicating that the miR-20b-5p/SDC2 axis is a potential target for reversing 5-FU resistance in CRC.