A ceRNA Circuitry Involving the Long Noncoding RNA Klhl14-AS, Pax8, and Bcl2 Drives Thyroid Carcinogenesis.

Abstract

<i>Klhl14-AS</i> is a long noncoding RNA expressed since early specification of thyroid bud and is the most enriched gene in the mouse thyroid primordium at E10.5. Here, we studied its involvement in thyroid carcinogenesis by analyzing its expression in cancer tissues and different models of neoplastic transformation. Compared with normal thyroid tissue and cells, <i>Klhl14-AS</i> was significantly downregulated in human thyroid carcinoma tissue specimens, particularly the anaplastic histotype, thyroid cancer cell lines, and rodent models of thyroid cancer. Downregulating the expression of <i>Klhl14-AS</i> in normal thyroid cells decreased the expression of thyroid differentiation markers and cell death and increased cell viability. These effects were mediated by the binding of <i>Klhl14-AS</i> to two miRNAs, <i>Mir182-5p</i> and <i>Mir20a-5p</i>, which silenced <i>Pax8</i> and <i>Bcl2</i>, both essential players of thyroid differentiation. <i>MIR182-5p</i> and <i>MIR20a-5p</i> were upregulated in human thyroid cancer and thyroid cancer experimental models and their effects on <i>Pax8</i> and <i>Bcl2</i> were rescued by <i>Klhl14-AS</i> overexpression, confirming <i>Klhl14-AS</i> as a ceRNA for both <i>Pax8</i> and <i>Bcl2</i>. This work connects deregulation of differentiation with increased proliferation and survival in thyroid neoplastic cells and highlights a novel ceRNA circuitry involving key regulators of thyroid physiology. SIGNIFICANCE: This study describes a new ceRNA with potential tumor suppression activity and helps us better understand the regulatory mechanisms during thyroid differentiation and carcinogenesis.