miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3.
The expression and function of miR-145 in thyroid cancer is unknown. We evaluated the expression and function of miR-145 in thyroid cancer and its potential clinical application as a biomarker. We found that the expression of miR-145 is significantly downregulated in thyroid cancer as compared with normal. Overexpression of miR-145 in thyroid cancer cell lines resulted in: decreased cell proliferation, migration, invasion, VEGF secretion, and E-cadherin expression. miR-145 overexpression also inhibited the PI3K/Akt pathway and directly targeted AKT3. In vivo, miR-145 overexpression decreased tumor growth and metastasis in a xenograft mouse model, and VEGF secretion. miR-145 inhibition in normal primary follicular thyroid cells decreased the expression of thyroid cell differentiation markers. Analysis of indeterminate fine-needle aspiration samples showed miR-145 had a 92% negative predictive value for distinguishing benign from malignant thyroid nodules. Circulating miR-145 levels were significantly higher in patients with thyroid cancer and showed a venous gradient. Serum exosome extractions revealed that miR-145 is secreted. Our findings suggest that miR-145 is a master regulator of thyroid cancer growth, mediates its effect through the PI3K/Akt pathway, is secreted by the thyroid cancer cells, and may serve as an adjunct biomarker for thyroid cancer diagnosis.
Endocrine Oncology BranchLaboratory of PathologyNational Cancer Institute, National Institutes of Health, Center for Cancer Research, Bethesda, Maryland 20892, USA.
Myriem
M
Boufraqech
Endocrine Oncology BranchLaboratory of PathologyNational Cancer Institute, National Institutes of Health, Center for Cancer Research, Bethesda, Maryland 20892, USA.
Lisa
L
Zhang
Endocrine Oncology BranchLaboratory of PathologyNational Cancer Institute, National Institutes of Health, Center for Cancer Research, Bethesda, Maryland 20892, USA.
Meenu
M
Jain
Endocrine Oncology BranchLaboratory of PathologyNational Cancer Institute, National Institutes of Health, Center for Cancer Research, Bethesda, Maryland 20892, USA.
Dhaval
D
Patel
Endocrine Oncology BranchLaboratory of PathologyNational Cancer Institute, National Institutes of Health, Center for Cancer Research, Bethesda, Maryland 20892, USA.
Ryan
R
Ellis
Endocrine Oncology BranchLaboratory of PathologyNational Cancer Institute, National Institutes of Health, Center for Cancer Research, Bethesda, Maryland 20892, USA.
Yin
Y
Xiong
Endocrine Oncology BranchLaboratory of PathologyNational Cancer Institute, National Institutes of Health, Center for Cancer Research, Bethesda, Maryland 20892, USA.
Mei
M
He
Endocrine Oncology BranchLaboratory of PathologyNational Cancer Institute, National Institutes of Health, Center for Cancer Research, Bethesda, Maryland 20892, USA.
Naris
N
Nilubol
Endocrine Oncology BranchLaboratory of PathologyNational Cancer Institute, National Institutes of Health, Center for Cancer Research, Bethesda, Maryland 20892, USA.
Maria J
MJ
Merino
Endocrine Oncology BranchLaboratory of PathologyNational Cancer Institute, National Institutes of Health, Center for Cancer Research, Bethesda, Maryland 20892, USA kebebewe@mail.nih.gov.
Electron
E
Kebebew
D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D019869:Phosphatidylinositol 3-Kinases; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt
AKT3; biomarker; metastasis; miR-145; thyroid cancer