Esposito, Matteo (2022) Investigating the role of Klhl14 in thyroid differentiation. [Tesi di dottorato]

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Abstract

Early molecular events of thyroid differentiation are not fully understood even though its organogenesis is well characterized. Over the last few decades, the recently described Kelch-like protein family caught the attention for its members ability to modulate differentiation processes and tumorigenesis by targeting specific protein for degradation. Klhl14, a member of this family, came out as one of the most enriched gene in E10.5 mouse thyroid bud, alongside with a previously uncharacterized lncRNA and Klhl14 natural antisense that was named by our group Thybe1/Klhl14-AS (as for thyroid bud enriched 1). Klhl14-AS has been recently described as a regulator of thyroid transcription factors and a modulator of Klhl14 expression, although little is known in Klhl14 involvement in thyroid differentiation. To understand Klhl14 role, in this work we characterized its capacity to modulate thyroid factors abundance in thyroid normal cells and to elicit a negative response in survivability and proliferation of thyroid transformed cells. We found that Klhl14 silencing does not only negatively affect thyroid specific protein abundance, but also increase the presence of Klhl14-AS, thyroid transcription factors FoxE1 and Pax8, and Bcl2, all described to regulate thyroid homeostasis. Moreover, Klhl14 alteration could also direct Nis and Thyroglobulin maturation and distribution in and out of the cell. Interestingly, we also observed a negative effect on thyroid transformed cells survival that is in line with a proposed tumor suppressor role of Klhl14 described in literature. In conclusion, we have described how the effects of tuning up or down Klhl14 expression in thyroid can induce a response that is likely to influence differentiation and homeostasis of this endocrine gland.

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