Abstract
Klhl14-AS 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, Klhl14-AS 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 Klhl14-AS 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 Klhl14-AS to two miRNAs, Mir182-5p and Mir20a-5p, which silenced Pax8 and Bcl2, both essential players of thyroid differentiation. MIR182-5p and MIR20a-5p were upregulated in human thyroid cancer and thyroid cancer experimental models and their effects on Pax8 and Bcl2 were rescued by Klhl14-AS overexpression, confirming Klhl14-AS as a ceRNA for both Pax8 and Bcl2. 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.
Highlights
The widest and least known part of human genome is extensively transcribed in noncoding RNA molecules, generally classified in short and long noncoding RNA based on their length
To investigate the involvement of KLHL14-AS in thyroid carcinogenesis, we analyzed its expression in 12 pairs of papillary thyroid cancer (PTC) specimens and their healthy adjacent tissue (HT) by Quantitative real-time PCR (qRT-PCR)
All tumor samples were compared with all healthy ones, showing that PTCs values are characterized by a median lower with respect to that of healthy thyroids (HT) (Fig. 1A)
Summary
The widest and least known part of human genome is extensively transcribed in noncoding RNA molecules, generally classified in short and long noncoding RNA based on their length. Long noncoding RNAs (lncRNA) are broadly defined as RNA molecules longer than 200 nucleotides that appear to lack protein-coding potential [1]. LncRNAs are functional molecules, acting through different mechanisms that can be generally reassumed into three types: guides, scaffolds, and molecular decoys. One abundant and wellstudied class of short RNAs are miRNAs (miRNA), 22–23 nt long RNA molecules that guide RNA-induced silencing complexes on target mRNAs and lncRNAs, to either block mRNA translation or induce target RNA decay [2, 3]. Several lncRNAs are able to regulate the expression of other RNAs sharing responsive elements for the same miRNA (MRE), acting as competitive endogenous RNA To protein-coding genes and miRNAs, lncRNAs are aberrantly expressed in cancer, affecting the complex regulatory circuits in which they are involved [7]. The miRNA sponge activity of several lncRNAs has been shown in different kinds of cancer, including thyroid cancer, where they play either oncogenic or tumor suppressor roles [8,9,10,11,12,13]
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