miR-22 inhibits tumor growth and metastasis by targeting ATP citrate lyase: evidence in osteosarcoma, prostate cancer, cervical cancer and lung cancer

MicroRNAs (miRNAs) are non-coding small RNAs that function as negative regulators of gene expression involving in the tumor biology. ATP citrate lyase (ACLY), a key enzyme initiating de novo lipid synthesis, has been found to be upregulated in cancer cells, and its inhibition causes suppressive effe...

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Bibliographic Details
Published in:Oncotarget 2016-07, Vol.7 (28), p.44252-44265
Main Authors: Xin, Mei, Qiao, Zhiguang, Li, Jing, Liu, Jianjun, Song, Shaoli, Zhao, Xiaoping, Miao, Ping, Tang, Tingting, Wang, Lei, Liu, Weichun, Yang, Xiaodi, Dai, Kerong, Huang, Gang
Format: Article
Language:English
Subjects:
Animals
Apoptosis - genetics
ATP Citrate (pro-S)-Lyase - antagonists & inhibitors
ATP Citrate (pro-S)-Lyase - genetics
ATP Citrate (pro-S)-Lyase - metabolism
Base Sequence
Cell Line, Tumor
Cell Proliferation - genetics
Disease Models, Animal
Female
Genetic Therapy - methods
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
MicroRNAs - genetics
MicroRNAs - pharmacology
Neoplasm Metastasis
Neoplasms - enzymology
Neoplasms - genetics
Neoplasms - pathology
Neoplasms - therapy
Random Allocation
Research Paper
Transfection
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Summary:MicroRNAs (miRNAs) are non-coding small RNAs that function as negative regulators of gene expression involving in the tumor biology. ATP citrate lyase (ACLY), a key enzyme initiating de novo lipid synthesis, has been found to be upregulated in cancer cells, and its inhibition causes suppressive effects in a variety of tumors. At present, although several ACLY inhibitors have been reported, the potential role of miRNAs in interfering ACLY still needs further clarification. Herein, four different types of tumor cells including osteosarcoma, prostate, cervical and lung cancers were adopted in our study, and we have demonstrated that miR-22 directly downregulated ACLY. Moreover, miR-22 was proved to attenuate cancer cell proliferation and invasion, as well as promote cell apoptosis via inhibiting ACLY. Additionally, we confirmed the higher ACLY protein levels and the lower miR-22 expressions in hundreds of clinical samples of the four primary tumors, and a negative correlation relationship between ACLY and miR-22 was clarified. Finally, in the four animal models, we found that along with the loss of the ACLY expression, the miR-22-treated mice developed rather smaller tumors, less probabilities of distant metastasis, and fairly longer survivals. De novo lipogenesis suppression triggered by miR-22-ACLY axis may contribute to the inhibition of tumor growth and metastasis. These findings provide unequivocal proofs that miR-22 is responsible for the posttranscriptional regulation of ACLY, which yields promising therapeutic effects in osteosarcoma, prostate, cervical and lung cancers.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.10020