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Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits
Medullary Thyroid Carcinoma
#MMPMID28119454
Song H
; Lin C
; Yao E
; Zhang K
; Li X
; Wu Q
; Chuang PT
J Biol Chem
2017[Mar]; 292
(9
): 3888-3899
PMID28119454
show ga
Among the four different types of thyroid cancer, treatment of medullary thyroid
carcinoma poses a major challenge because of its propensity of early metastasis.
To further investigate the molecular mechanisms of medullary thyroid carcinoma
and discover candidates for targeted therapies, we developed a new mouse model of
medullary thyroid carcinoma based on our CGRP(CreER) mouse line. This system
enables gene manipulation in parafollicular C cells in the thyroid, the purported
cells of origin of medullary thyroid carcinoma. Selective inactivation of tumor
suppressors, such as p53, Rb, and Pten, in mature parafollicular C cells via an
inducible Cre recombinase from CGRP(CreER) led to development of murine medullary
thyroid carcinoma. Loss of Pten accelerated p53/Rb-induced medullary thyroid
carcinoma, indicating interactions between pathways controlled by tumor
suppressors. Moreover, labeling differentiated parafollicular C cells by
CGRP(CreER) allows us to follow their fate during malignant transformation to
medullary thyroid tumor. Our findings support a model in which mutational events
in differentiated parafollicular C cells result in medullary thyroid carcinoma.
Through expression analysis including RNA-Seq, we uncovered major signaling
pathways and networks that are perturbed following the removal of tumor
suppressors. Taken together, these studies not only increase our molecular
understanding of medullary thyroid carcinoma but also offer new candidates for
designing targeted therapies or other treatment modalities.
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