Thyroglobulin increases thyroid cell proliferation via the suppression of specific microRNAs.
Thyroglobulin (Tg), stored in the follicular lumen, has also been shown recently to perform two unexpected roles: as an autocrine negative-feedback suppressor of thyroid function in the presence of TSH and as a potent inducer of thyroid cell growth in the absence of TSH. However, the underlying molecular mechanism(s) remain unclear. To elucidate a molecular pathway linking Tg to increased cell proliferation, we examined the regulation of microRNAs (miRNAs) by Tg using an miRNA microarray. We identified 21 miRNAs whose expression was significantly suppressed by Tg in rat thyroid FRTL-5 cells. Using specific miRNA analogs, we determined that miR-16, miR-24, and miR-195 mediate the induction of thyroid cell growth by Tg. The expression of miR-16 and miR-195 target genes, Mapk8, Ccne1, and Cdc6, which were previously shown to be essential for TSH-stimulated thyroid cell growth, were also induced by Tg. Moreover, the Tg-induced expression of these genes was reduced by overexpression of miR-16 and miR-195. Similarly, the induction of c-Myc by Tg was reduced by miR-24 overexpression. These results suggest that Tg could alter thyroid cell proliferation by increasing the expression of cell division-related genes such as Mapk8, Ccne1, Cdc6, and c-Myc through its suppression of specific microRNAs (miR-16, miR-24, and miR-195). In addition, we identified phosphatidylinositol 3-kinase as a key signaling pathway, linking Tg with cell proliferation. The present data support an important role for miRNAs as effectors for the effect of Tg on cell proliferation and perhaps other functions of Tg in the thyroid cell.
Laboratory of Molecular Diagnostics (T.A., Y.L., A.K., K.T., A.Y, Y.I., K.N., K.S.), Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Higashimurayama-shi, Tokyo 189-0002, Japan; Department of Medicine, Uniformed Services University of the Health Sciences (D.F.S.), Bethesda, Maryland 20814-4799; and Department of Pharmacology, National Research Institute for Child Health and Development (K.N., A.T.), Setagaya-ku, Tokyo 157-8538, Japan.
Takeshi
T
Akama
Yuqian
Y
Luo
Donald F
DF
Sellitti
Akira
A
Kawashima
Kazunari
K
Tanigawa
Aya
A
Yoshihara
Yuko
Y
Ishido
Kazuaki
K
Nakamura
Akito
A
Tanoue
Koichi
K
Suzuki
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D013954:Thyroglobulin / Q000502:physiology*; D013961:Thyroid Gland / Q000166:cytology*; D059467:Transcriptome
D018797:Cell Cycle Proteins; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D013954:Thyroglobulin; D019869:Phosphatidylinositol 3-Kinases