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

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.

Sexual Dimorphism of miRNAs Secreted by Bovine In vitro-produced Embryos

“…A study by Feng et al (2015) identified that presence of miR-320 in the human follicular fluid is decreased in patients using intracytoplasmic sperm injection to conceive, and knockdown of miR-320 in mouse oocytes negatively affects developmental potential of embryos through inhibition of the Wnt signaling pathway. Additionally, miR-22 functions in human cells during apoptosis — a process which is known to be differentially regulated between male and female blastocysts (Ghys et al, 2016; Oliveira et al, 2016), suppressing tumor growth through inhibition of ATP citrate lyase (Xin et al, 2016). Further, miR-22 has been observed in media of bovine embryos which degenerate prematurely, failing to successfully form blastocysts (Kropp and Khatib, 2015).…”

Response of MiRNA-22-3p and MiRNA-149-5p to Folate Deficiency and the Differential Regulation of MTHFR Expression in Normal and Cancerous Human Hepatocytes

“…MiR-22 has been determined to be a regulator or an inhibitor in diverse cancers, including osteosarcoma, prostate cancer, cervical cancer, lung cancer, [44]breast cancer[45], colorectal cancer[46], gastric cancer [47, 48], ovarian cancer[49], acute myeloid leukemia[50], medulloblastomas[51], endometrial endometrioid carcinomas[52], esophageal squamous cell carcinoma[53] and hepatocellular carcinoma[54]. The study by Zhou et al [55] found that miR-22 is downregulated in HCC and that its expression is associated with the differentiation, metastasis and prognosis of carcinomas.…”

Molecular mechanisms and clinical applications of miR-22 in regulating malignant progression in human cancer (Review)

“…Congruently, miR-22 could cut off energy metabolism by directly silencing GLUT1 (glucose transporter protein type 1), a protein unidirectionally transferring glucose into the cytoplasm to promote energy metabolism, and ACLY (ATP citrate lyase), an enzyme accelerating lipid synthesis and elevated expression in cancers, restraining cancer proliferation, migration and invasion and inducing apoptosis, which is negatively linked to TNM stage, metastasis, recurrence and survival rates of breast, prostate, osteosarcoma, lung and cervical cancers (10,11). Moreover, miR-22 has low expression in colorectal cancer (CRC), and increased expression of miR-22 to silence HIF-1α (hypoxia inducible factor 1α) may severely repress VEGF (vascular endothelial growth factor) expression to block angiogenesis, leading to the disruption of cancer progression (12) (Fig.…”