Disrupted in Renal Carcinoma 3(DIRC3) impacts malignant phenotype and IGFBP5/IGF-1/Akt signaling axis in differentiated thyroid cancer

Abstract

ABSTRACTDifferentiated thyroid cancers (DTCs) are malignancies with ill-defined hereditary predisposition. Some germline variants influencing the risk of DTCs localize indisrupted in renal carcinoma 3(DIRC3), a poorly characterized long non-coding RNA (lncRNA) gene. Here, we characterized the function ofDIRC3in DTCs. We established thatDIRC3is downregulated in DTCs, and its high expression may reduce the risk of cancer recurrence in patients.DIRC3transcripts were enriched in cell nucleiin vitro, where they upregulatedinsulin-like growth factor binding protein 5(IGFBP5), a gene known to modulate the cellular response to insulin-like growth factor 1 (IGF-1). Silencing ofDIRC3in thyroid cancer cell lines produced a phenotypic dichotomy: it augmented cell migration and invasiveness, reduced apoptosis, but abrogated the MTT reduction rate. We demonstrated that the pro-migratory phenotype was produced by the downregulation ofIGFBP5. Transcriptomic profiling confirmed a functional redundancy in the activities ofDIRC3andIGFBP5. Moreover, downregulation ofDIRC3enhanced the susceptibility of cancer cells to IGF-1 stimulation and promoted Akt signaling. In conclusion,DIRC3expression alters the phenotype of thyroid cancer cells and modulates the activity of IGFBP5/IGF-1/Akt axis. We propose an interplay betweenDIRC3and IGF signaling as a mechanism that promotes thyroid carcinogenesis.