miR-22 inhibits tumor growth and metastasis by targeting ATP citrate lyase: evidence in osteosarcoma, prostate cancer, cervical cancer and lung cancer
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Mei Xin1,*, Zhiguang Qiao2,*, Jing Li3,4,*, Jianjun Liu1, Shaoli Song1, Xiaoping Zhao1, Ping Miao1, Tingting Tang2, Lei Wang2, Weichun Liu5, Xiaodi Yang6, Kerong Dai2,7, Gang Huang1,8
1Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
2Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
3Bone and Joint Research Center, The First Affiliated Hospital, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710061, China
4Department of Orthopaedics, Alpert Medical School/Rhode Island Hospital, Brown University, Providence, RI 02903, USA
5Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
6Department of Anesthesiology, Zhongshan Hospital, School of Medicine, Fudan University, Shanghai 200032, China
7The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China
8Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, 200031, China
*These authors have contributed equally to this work
Gang Huang, email: firstname.lastname@example.org
Kerong Dai, email: email@example.com
Keywords: miR-22, ACLY, metabolism, tumor, therapy
Received: September 22, 2015 Accepted: May 11, 2016 Published: June 14, 2016
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.
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