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Updated: Jun 23, 2025
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
KLHL14 is a tumor suppressor downregulated in undifferentiated thyroid cancer
Matteo Esposito1,2, Antonella Migliaccio1, Sara Carmela Credendino1
1Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli Federico II, Via Pansini 5, 80131, Napoli, Italy.
Abstract:
KLHL14 is a substrate-binding subunit of Cullin-RING ligase 3 ubiquitin ligase complex, highly enriched in thyroid since early embryonic development, together with its antisense RNA KLHL14-AS. We have previously demonstrated that Klhl14-AS is a competing endogenous RNA regulating several differentiation and survival factors in thyroid cancer, acting as tumor suppressor. Recently, also KLHL14 has been shown to function as tumor suppressor in diffuse large B-cell lymphoma and in malignant mesothelioma. Here we show that KLHL14 expression is strongly reduced in anaplastic thyroid cancer, the less differentiated and most aggressive type of thyroid neoplasia. Such reduction is reproduced in different in vivo and in vitro models of thyroid cancer, being invariably associated with loss of differentiation. When Klhl14 expression is rescued in thyroid transformed cells, it reduces the cell proliferation rate and increase the number of apoptotic cells. On the other side, Klhl14 loss of function in normal thyroid cells affects the expression of several regulatory as well as functional thyroid markers. All these findings suggest that KLHL14 could be considered as a novel tumor suppressor in thyroid cancer, by also revealing its physiological role in the maintenance of a fully differentiated and functional thyroid phenotype.
Insights
Kelch-like protein 14 (KLHL14) acts as a tumor suppressor in thyroid cancer, with reduced expression linked to aggressive, undifferentiated tumors. Restoring KLHL14 inhibits cancer cell growth and promotes apoptosis, highlighting its role in thyroid cell differentiation.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Kelch-like protein 14 (KLHL14) is a component of the Cullin-RING ligase 3 complex, crucial in thyroid development.
- Its antisense RNA, KLHL14-AS, functions as a tumor suppressor in thyroid cancer.
- KLHL14 itself has demonstrated tumor suppressor activity in other cancers like lymphoma and mesothelioma.
Purpose of the Study:
- To investigate the role of KLHL14 in thyroid cancer, particularly in anaplastic thyroid cancer.
- To determine the impact of KLHL14 expression levels on thyroid cancer cell differentiation, proliferation, and apoptosis.
- To elucidate the physiological function of KLHL14 in normal thyroid tissue.
Main Methods:
- Analysis of KLHL14 expression in anaplastic thyroid cancer tissues and cell models.
- In vivo and in vitro experiments using thyroid cancer models to study KLHL14 function.
- Rescue experiments to restore KLHL14 expression in transformed thyroid cells.
- Loss-of-function studies in normal thyroid cells.
Main Results:
- KLHL14 expression is significantly reduced in anaplastic thyroid cancer, correlating with dedifferentiation.
- Reduced KLHL14 expression was observed in various in vivo and in vitro thyroid cancer models.
- Restoring KLHL14 expression decreased proliferation and increased apoptosis in thyroid cancer cells.
- Loss of KLHL14 function in normal thyroid cells altered key regulatory and functional markers.
Conclusions:
- KLHL14 acts as a novel tumor suppressor in thyroid cancer.
- KLHL14 plays a critical role in maintaining thyroid cell differentiation and function.
- KLHL14 deficiency is associated with aggressive, less differentiated thyroid neoplasia.
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