Original ArticlesmiR-22 as a prognostic factor targets glucose transporter protein type 1 in breast cancer
Introduction
Breast cancer is one of the most common malignant diseases in women worldwide [1]. Although improvements in detection and treatment have decreased breast cancer mortality in recent years, the prevention and therapy of breast cancer remain a major public health concern [2]. MicroRNAs (miRNAs) are a class of small non-coding RNAs (18~22 nt) that silence their cognate target genes by either degrading mRNA molecules or inhibiting their translation [3]. They can act as oncogenes or tumor suppressors and are often dysregulated in tumors [4], [5]. These dysregulations are believed to be involved in cancer progression and can be prognostically indicative of human cancers. Increasing studies show that miRNAs are involved in the tumorigenesis and progression of breast cancer. In this study, we focus on miR-22, which has been found to be aberrant in a variety of cancers, overexpressed in prostate cancer, and down-regulated in cholangiocarcinoma, multiple myeloma, colorectal cancer, and hepatocellular carcinoma [6], [7]. In a previous study, we found that the over-expression of miR-22 can inhibit gastric cancer cell growth in vitro and in vivo and induces apoptosis through targeting the Wnt-1 signaling pathway [8]. Moreover, the up-regulation of miR-22 expression has been reported to suppress gastric cancer cell migration and invasion by targeting the Sp1 gene [9]. In addition, miR-22 has been shown to inhibit estrogen signaling by directly targeting the estrogen receptor alpha mRNA [10], and its overexpression induces growth suppression and senescence-like phenotypes in human breast epithelial and cancer cells [11].
Cancer cells utilize glucose as the main energy substrate using only these facilitative transport systems (GLUTs) based on their increased metabolic activity and rapid proliferation [12]. Glucose transporter 1, which is also known as solute carrier family 2 (SLC2A1), facilitates glucose transporter member 1 (GLUT1), a uniporter protein that is encoded by the SLC2A1/GLUT1 gene in humans [13]. GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells. Previous literature has reported that GLUT1 expression is associated with increased malignant potential, invasiveness, and poor prognosis in lung, colorectal, gastric, and ovarian cancers. In addition, GLUT1 expression is increased in breast cancer with higher grade and proliferative activity [14]. In this study, we proved that miR-22 can directly target the GLUT1 gene, and its expression is negatively correlated with GLUT1 expression in breast cancer. Moreover, the correlation of miR-22 and GLUT1 expression is a valuable marker of breast cancer prognosis.
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Cell culture
The human breast cancer cell lines MDA-MB-231 and MCF-7, which were obtained from American Type Culture Collection and freshly recovered from liquid nitrogen (3 months), were cultured in Dulbecco's modified Eagle's medium (DMEM, Invitrogen, CA, USA) supplemented with 10% fetal bovine serum (FBS, GIBCO, Cappinas, Brazil) in a humidified incubator at 37 °C containing 5% CO2.
Clinical samples
Paraffin-embedded tumor tissues were obtained from 122 female breast cancer patients who were diagnosed by two pathologists
SLC2A1/GLUT1 is a direct target of miR-22
We used two algorithms (TargetScan and Miranda) to identify the miR-22 targets in human breast cancer. Among these candidate target genes, both algorithms predicted SLC2A1 (Fig. 1A), which provides instructions for producing glucose transporter protein type 1 (GLUT1). We confirmed this finding in breast cancer cell lines by performing luciferase reporter assays. The full-length GLUT1 3′-UTR was cloned downstream of the firefly luciferase gene and cotransfected with miR-22 mimics or scrambled
Discussion
Breast cancer is a group of heterogeneous diseases that show various biological and clinical characteristics [16]. MiRNAs have been demonstrated to have a close relationship with breast cancer. For instance, in breast cancer, miR-200c restores sensitivity to microtubule-targeting chemotherapeutic agents [17], and miR-31 inhibits local invasion, extravasation, or initial survival at a distant site and metastatic colonization [18]. miR-22 was originally identified in HeLa cells and has been shown
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgments
This work was supported by funds from the National Natural Science Foundation of China (31100935, 81302318, and 81272514), the Key Program of National Natural Science Foundation of China (31030061), and the China Postdoctoral Science Foundation (2012M520075).
References (24)
MicroRNAs: target recognition and regulatory functions
Cell
(2009)- et al.
Diallyl disulfide suppresses proliferation and induces apoptosis in human gastric cancer through Wnt-1 signaling pathway by up-regulation of miR-200b and miR-22
Cancer Lett
(2013) - et al.
Glut-1 expression correlates with basal-like breast cancer
Transl. Oncol
(2011) - et al.
Differentiation-associated miR-22 represses Max expression and inhibits cell cycle progression
Biochem. Biophys. Res. Commun
(2010) - et al.
Cancer statistics, 2013
CA Cancer J. Clin
(2013) - et al.
Metastatic breast cancer, version 1.2012: featured updates to the NCCN guidelines
J. Natl. Compr. Canc. Netw
(2012) - et al.
MicroRNAs: cobblestones on the road to cancer metastasis
Crit. Rev. Oncog
(2013) - et al.
miRNAs as modulators of angiogenesis
Cold Spring Harb. Perspect. Med
(2013) - et al.
microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity
Br. J. Cancer
(2010) - et al.
Clinical significance of miR-22 expression in patients with colorectal cancer
Med. Oncol
(2012)
miR-22 is down-regulated in gastric cancer, and its overexpression inhibits cell migration and invasion via targeting transcription factor Sp1
Med. Oncol
miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA
Mol. Cell. Biol
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These authors contributed equally to this work.