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

Differentiated thyroid cancers (DTCs) are malignancies with ill-defined hereditary predisposition. Some germline variants influencing the risk of DTCs localize in disrupted in renal carcinoma 3 ( DIRC3 ), a poorly characterized long non-coding RNA (lncRNA) gene. Here, we characterized the function of DIRC3 in DTCs. We established that DIRC3 is downregulated in DTCs, and its high expression may reduce the risk of cancer recurrence in patients. DIRC3 transcripts were enriched in cell nuclei in vitro , where they upregulated insulin-like growth factor binding protein 5 ( IGFBP5 ), a gene known to modulate the cellular response to insulin-like growth factor 1 (IGF-1). Silencing of DIRC3 in 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 of IGFBP5 . Transcriptomic profiling confirmed a functional redundancy in the activities of DIRC3 and IGFBP5 . Moreover, downregulation of DIRC3 enhanced the susceptibility of cancer cells to IGF-1 stimulation and promoted Akt signaling. In conclusion, DIRC3 expression alters the phenotype of thyroid cancer cells and modulates the activity of IGFBP5/IGF-1/Akt axis. We propose an interplay between DIRC3 and IGF signaling as a mechanism that promotes thyroid carcinogenesis. ### Competing Interest Statement The authors have declared no competing interest. * DTC : differentiated thyroid cancers cPTC : conventional papillary thyroid cancer DEG : differentially expressed gene DIRC3 : disrupted in renal carcinoma 3 ERK : extracellular signal-regulated kinase FBS : fetal bovine serum FOV : field of view FTC : follicular thyroid cancer fvPTC : follicular variant papillary thyroid cancer GO : gene ontology GTEx : Genotype-Tissue Expression (project) GWAS : genome-wide association study HTC : Hürthle cell thyroid cancer IGF-1 : insulin-like growth factor 1 IGF-1R : insulin-like growth factor 1 receptor IGFBP5 : insulin-like growth factor binding protein 5 lncRNA : long non-coding RNA PTC : papillary thyroid cancer SD : standard deviation SNP : single nucleotide polymorphism TCGA : The Cancer Genome Atlas (project)