Cancer Letters

Cancer Letters

Volume 356, Issue 2, Part B, 28 January 2015, Pages 410-417
Cancer Letters

Original Articles
miR-22 as a prognostic factor targets glucose transporter protein type 1 in breast cancer

https://doi.org/10.1016/j.canlet.2014.09.028Get rights and content

Abstract

It has been reported that miR-22 plays an important role and may be a promising therapeutic target in cancer. In this study, we found that GLUT1 is a direct target of miR-22. The ectopic expression of miR-22 inhibited breast cancer cell proliferation and invasion by targeting GLUT1. A reverse correlation between the expression of miR-22 and GLUT1 was observed in breast cancer tissue samples. Furthermore, miR-22 was significantly correlated with the TNM stage, local relapse, distant metastasis, and survival of breast cancer patients. Our data suggest that miR-22 functions as a tumor suppressor and is a promising prognostic biomarker 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.

Section snippets

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)

  • M.M. Guo et al.

    miR-22 is down-regulated in gastric cancer, and its overexpression inhibits cell migration and invasion via targeting transcription factor Sp1

    Med. Oncol

    (2013)
  • D.P. Pandey et al.

    miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA

    Mol. Cell. Biol

    (2009)
  • Cited by (78)

    • MicroRNA-22 in female malignancies: Focusing on breast, cervical, and ovarian cancers

      2021, Pathology Research and Practice
      Citation Excerpt :

      Overexpression of GLUT1 in breast cancer with greater grade has been reported. High GLUT1 and low miR-22 expression levels are associated with poor overall survival in patients with breast cancer, which suggests their expression could be a promising prognostic biomarker in breast cancer [46]. Dysregulated miRNAs mediate malignant phenotypes, such as metabolic reprogramming.

    • Metabolic reprogramming and immunity in cancer

      2021, Cancer Immunology and Immunotherapy: Volume 1 of Delivery Strategies and Engineering Technologies in Cancer Immunotherapy
    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    View full text