TY - JOUR
T1 - Effects of let-7 microRNA on cell growth and differentiation of papillary thyroid cancer
AU - Ricarte-Filho, Júlio Cezar Marques
AU - Fuziwara, Cesar Seigi
AU - Yamashita, Alex Shimura
AU - Rezende, Eloiza
AU - Da-Silva, Marley Januário
AU - Kimura, Edna Teruko
N1 - Funding Information:
Address all correspondence to: Edna T. Kimura, MD, PhD, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, 05508-000 São Paulo, SP, Brazil. E-mail: etkimura@usp.br 1This study was supported by research grants and a doctoral fellowship from the Foundation for Research Support of the State of São Paulo (FAPESP), Technological and Scientific Development National Council (CNPq), and the Coordination for the Improvement of Higher Education Personnel (CAPES). 2These authors contributed equally to this article. Received 24 April 2009; Revised 27 June 2009; Accepted 29 June 2009 Copyright © 2009 Neoplasia Press, Inc. Open access under CC BY-NC-ND license. 1944-7124 DOI 10.1593/tlo.09151
PY - 2009
Y1 - 2009
N2 - Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy and RET/PTC rearrangements represent key genetic events frequently associated to this cancer, enhancing proliferation and dedifferentiation by activation of the RET/PTC-RAS-BRAF-mitogen-activated protein kinase (MAPK) pathway. Recently, let-7 microRNA was found to reduce RAS levels in lung cancer, acting as a tumor suppressor gene. Here, we report that RET/PTC3 oncogenic activation in PCCL3 rat thyroid cells markedly reduces let-7f expression. Moreover, stable transfection of let-7 microRNA in TPC-1 cells, which harbor RET/PTC1 rearrangement, inhibits MAPK activation. As a result, let-7f was capable of reducing TPC-1 cell growth, and this might be explained, at least in part, by decreased messenger RNA (mRNA) expression of cell cycle stimulators such as MYC and CCND1 (cyclin D1) and increased P21 cell cycle inhibitor mRNA. In addition, let-7 enhanced transcriptional expression ofmolecular markers of thyroid differentiation such as TITF1 and TG. Thus, reduced expression of let-7f might be an essential molecular event in RET/PTC malignant transformation. Moreover, let-7f effects on thyroid growth and differentiation might attenuate neoplastic process of RET/PTC papillary thyroid oncogenesis through impairment of MAPK signaling pathway activation. This is the first functional demonstration of an association of let-7 with thyroid cancer cell growth and differentiation.
AB - Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy and RET/PTC rearrangements represent key genetic events frequently associated to this cancer, enhancing proliferation and dedifferentiation by activation of the RET/PTC-RAS-BRAF-mitogen-activated protein kinase (MAPK) pathway. Recently, let-7 microRNA was found to reduce RAS levels in lung cancer, acting as a tumor suppressor gene. Here, we report that RET/PTC3 oncogenic activation in PCCL3 rat thyroid cells markedly reduces let-7f expression. Moreover, stable transfection of let-7 microRNA in TPC-1 cells, which harbor RET/PTC1 rearrangement, inhibits MAPK activation. As a result, let-7f was capable of reducing TPC-1 cell growth, and this might be explained, at least in part, by decreased messenger RNA (mRNA) expression of cell cycle stimulators such as MYC and CCND1 (cyclin D1) and increased P21 cell cycle inhibitor mRNA. In addition, let-7 enhanced transcriptional expression ofmolecular markers of thyroid differentiation such as TITF1 and TG. Thus, reduced expression of let-7f might be an essential molecular event in RET/PTC malignant transformation. Moreover, let-7f effects on thyroid growth and differentiation might attenuate neoplastic process of RET/PTC papillary thyroid oncogenesis through impairment of MAPK signaling pathway activation. This is the first functional demonstration of an association of let-7 with thyroid cancer cell growth and differentiation.
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U2 - 10.1593/tlo.09151
DO - 10.1593/tlo.09151
M3 - Article
C2 - 19956384
AN - SCOPUS:77950841115
VL - 2
SP - 236
EP - 241
JO - Translational Oncology
JF - Translational Oncology
SN - 1936-5233
IS - 4
ER -