Abstract
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.
Highlights
Cancer is one of the most devastating diseases that threats global human public health and life quality
MiR-22, in particular, yielded a notable and consistent decline in the four tumor cells (Figure 1B). These findings indicated a potent functional connection between ATP citrate lyase (ACLY) and miR-22, whose binding site was conserved across many other mammalian species (Figure 1C)
Our results showed that in the Saos-2 cell lines, the ACLY protein levels dropped by around 50% after the miR-22 mimic transfection compared to the negative control (NC)-treated cells, while the introduction of an overexpression plasmid could largely counteract the inhibitory effects that miR-22 exerted on ACLY
Summary
Cancer is one of the most devastating diseases that threats global human public health and life quality. Lung cancer has both the highest incidence and death rates in males, as well as the second leading cause of cancer deaths among females [1, 2]. Prostate cancer is the second most frequently diagnosed cancer that accounts for the fifth place of lethal cancerous disease in males worldwide [3]. Cervical cancer is the fourth most common cancer among women, with about 70% of the cases occurring in developing countries [2, 3]. It is a globally extreme urgency to develop effective approaches for treating these cancers
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