Background <p>Dysregulation of RNA-binding proteins (RBP) is closely associated with tumorigenesis. However, the regulatory mechanism of SOX2, a novel RBP, in non-small cell lung cancer (NSCLC) remains unclear.</p> Methods <p>LinkedOmics queried the correlation between CBLC and SOX2 expression. starBase predicted the targeting relationship between CBLC and SOX2, which was further determined by RIP and dual-luciferase reporter gene assays. mRNA decay assay was used to detect the mRNA decay rate of CBLB. RT-qPCR and Western Blot detected SOX2 and CBLC levels in tumor samples and NSCLC cell lines. A549 cells were cultured using gradient concentrations of DDP to establish an in vitro NSCLC resistance model. CCK-8 and colony formation assays were performed to detect the effects of SOX2 and CBLC on the proliferation of A549/DDP cells and DDP IC50. Flow cytometry was performed to detect apoptosis of A549/DDP cells. Transwell assay was performed to detect migration and invasion of A549/DDP cells. An in vivo model of NSCLC was established in mice. HE staining was performed to observe tumor metastatic nodules in the liver tissues of mice.</p> Results <p>Silencing SOX2 or CBLC significantly inhibited the proliferation, invasion, migration and metastasis of NSCLC cells and promoted tumor cell apoptosis and DDP sensitivity. Reducing SOX2 significantly inhibited the growth and distal metastasis of transplanted tumors in mice. SOX2 binding to the 3′UTR of CBLC affected the mRNA stability of CBLC. Overexpressing CBLC impaired SOX2 knockdown-induced inhibition of tumor cell proliferation and migration.</p> Conclusion <p>SOX2 is overexpressed in NSCLC tissues. Silencing of SOX2 in NSCLC cells inhibits DDP resistance and distal metastasis in NSCLC via CBLC.</p>