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

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.

• Authors: Sara C Credendino, Maria L Bellone, Nicole Lewin, Elena Amendola, Remo Sanges, Swaraj Basu, Romina Sepe, Myriam Decaussin-Petrucci, Nadia Tinto, Alfredo Fusco, Mario De Felice, Gabriella De Vita
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 22 Pg. 5746-5757 (Nov 15 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 31558562 (Publication Type: Journal Article)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• BCL2 protein, human
• Biomarkers, Tumor
• MicroRNAs
• PAX8 Transcription Factor
• PAX8 protein, human
• Proto-Oncogene Proteins c-bcl-2
• RNA, Long Noncoding

Topics

• Animals
• Biomarkers, Tumor (genetics)
• Carcinogenesis (genetics, pathology)
• Cell Death (genetics)
• Cell Differentiation (genetics)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cell Survival (genetics)
• Down-Regulation (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• HeLa Cells
• Humans
• Mice
• Mice, Transgenic
• MicroRNAs (genetics)
• PAX8 Transcription Factor (genetics)
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• RNA, Long Noncoding (genetics)
• Thyroid Gland (pathology)
• Thyroid Neoplasms (genetics, pathology)
• Up-Regulation (genetics)