Molecular assays showed that piR-54265 binds PIWIL2 protein to induce the formation of PIWIL2/STAT3/phosphorylated-SRC (p-SRC) complex, which promotes the STAT3 signaling pathway activation that subsequently leads to the cell proliferation, metastasis, and chemoresistance observed in CRC cells. Here, PIR is linked to colorectal carcinoma.