LNC473 regulating APAF1 IRES-dependent translation via competitive sponging miR574 and miR15b: Implications in colorectal cancer

Abstract Accumulating studies focused on the involvement of non-coding RNAs (ncRNAs) in the internal ribosome entry sites (IRES) mediated translation in tumorigenesis, however, its underlying mechanisms in colorectal cancer (CRC) remain elusive. Here, we unveiled that LINC00473 (LNC473) exerted its functions as a tumor suppressor in promoting APAF1 IRES activity through competitively sponging miR574-5p and miR15b-5p in CRC initiation and pathogenesis. Specifically, LNC473 and its downstream target APAF1 were significantly downregulated accompanied by upregulated miR574-5p and miR15b-5p in CRC cells and tissues, which had a significant prognostic impact on clinical outcomes in our CRC cohort (n = 157). Furthermore, ectopic LNC473 significantly sponged endogenous miR574-5p or miR15b-5p and thereby inhibited cell proliferation, colony formation capacity, and accelerated cell apoptosis through activating APAF1-CASP9-CASP3 pathway. Notably, LNC473 overexpression resulted in dramatical promotion of APAF1 IRES activity and translation, whereas rescue experiments confirmed the recovery by the existence of LNC473 and miR574/15b-5p. Mechanistically, LNC473 overexpression promoted IRES binding domain exposure and removed the constraints controlling from miR574-5p and miR15b-5p, subsequently enhanced IRES-mediated APAF1 expression in vitro and in vivo. Therefore, our results uncover a novel LNC473⊣miR574/miR15b-APAF1 signaling axis, which provides new targets and crosstalk regulation mechanism for CRC prevention and treatment.