In the present study, we show that ECM1a activates AKT/FAK/Paxillin/Rac/cytoskeletal signaling and upregulates CD326 expression to control tumorigenesis and cisplatin resistance through Gly-Pro-Arg (GPR) motif-mediated interactions with integrin αXβ2, heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL)-mediated alternative mRNA splicing, and ATP binding cassette subfamily G member 1 (ABCG1)-induced upregulation of cancer cell stemness. This evidence concerns the gene HNRNPLL and cancer.