Cell specific tumor suppressor effect of Hsa-miR-1226-3p through downregulation of HER2, PIK3R2, and AKT1 genes
Introduction
Regardless of the great progress in therapy, breast cancer is still one of the main causes of death in women across the globe with 25 % of all cancer cases and 15 % of all cancer-associated mortality (Sun et al., 2017). Four subtypes for breast cancer are known as HER2-positive (HER2-like), ER-negative/HER2-negative (basal-like), and low- and high-proliferative ER-positive/HER2-negative (luminal A and B, respectively). Recent studies reported that HER2 positive breast cancer has a higher incidence in Asian women compared with European women (Pathmanathan et al., 2016).
Her2 is a transmembrane protein that is encoded by HER2 oncogene and is located at 17q21-22 chromosome (Kwa et al., 2017). Her1, Her2, Her3, and, Her4 are also known as (EGFR/ErbB1, HER2/Neu, ErbB3, ErbB4, respectively) and are four members of ERBB class of receptor tyrosine kinases. These cell surface proteins are normally involved in epithelial cell survival and growth (Wieduwilt and Moasser, 2008). Furthermore, HER2 gene amplification and overexpression have been shown to be responsible for aggressive metastatic breast cancer (Yarden, 2001). Through cell surface interaction of Her2 receptor with hormones, cytokines, growth factors, and other extracellular signaling molecules, Her2 signaling pathway is activated which in downstream, leads to proliferation, differentiation, survival and cell migration (De Luca et al., 2012; Lemmon and Schlessinger, 2010).
Her family monomers have several domains including extracellular (N-terminal), transmembrane and cytoplasmic kinase domains. Autophosphorylation of specific tyrosine residues within the catalytic kinase domain of Her2 occurs upon the binding of ligand which induces homodimerization or heterodimerization of it (Hynes, 2016). Cell signaling such as MAPK, PI3K/AKT, and phospholipase Cγ pathways are activated following Her2 dimer complex activation (Liu et al., 2008). PI3K kinas phosphorylates 4, 5-diphosphate (PIP2) to phosphatidylinositol 3, 4, 5-triphosphate (PIP3) which in turn activates its downstream Akt (P. Liu et al., 2009). Phosphorylated Akt targets mTOR which eventually ends up with inhibition of apoptosis and stimulation of cell proliferation (Oh and Jacinto, 2011). To date, no specific ligand has been discovered for Her2 receptor and that’s the reason why Her2 tends to form potent heterodimers with EGFR and Her3 (Butti et al., 2018).
MicroRNAs are a category of short noncoding RNAs which regulate gene expression at the transcriptional or post-transcriptinal levels (Tani et al., 2012). Direct interaction between miRNA and target mRNAs occurs through base pairing of their complementary sites presented in 3′UTR, CDS and 5′UTR (Guo et al., 2010). If miRNA targets 3′UTR, it usually recruits RISC to the sequence and downregulates the expression (Seol et al., 2012). However, interaction of miRNA with coding sequences of mRNA might result in overexpression of the target gene (Wongfieng et al., 2017). Aberrant expression of miRNAs has been reported in several malignancies such as breast cancer (Mishra et al., 2015). In the present study we evaluated the effect of miR-1226-3p on PI3K/AKT pathway in breast cancer.
Section snippets
Bioinformatics study
In order to find the putative target genes that miR-1226-3p may regulates, a bioinformatics search was conducted. The miRNA expression analysis of breast cancer cell lines and tissues was adopted from GEO (GSE26659/26666/40525/81000/40059) (https://www.ncbi.nlm.nih.gov/geo/) database. The miRNA targets were predicted using TargetScan (http://www.targetscan.org/vert_71/), DIANA-microT (http://diana.cslab.ece.ntua.gr/pathways/), miRWalk (http://zmf.umm.uni-heidelberg.de/apps/zmf/mirwalk2/) and
Hsa-miR-1226 as a candidate regulator of PI3K/AKT signaling pathway in breast cancer
In order to investigate about the miRNAs that are capable of regulating PI3K/AKT signaling pathway, Targetscan, DIANA and miRWalk bioinformatics tools were used. Several miRNA recognition sites (MREs) specific for miR-1226-3p were predicted within the 3′UTR sequences of HER2, PIK3R2 and AKT1 genes (Fig. 1A). Six, Six, and three MREs were predicted within the 3′UTR sequences of HER2, PIK3R2, and AKT1 genes, respectively. Compared to the adjacent sequences within 3′UTRs, some of these MREs were
Discussion
Her2 is an important tyrosine kinase receptor that is involved in development of breast cancer and is considered as a switch to turn on PI3K/AKT signaling pathway. This pathway serves as a key regulator of cell survival, proliferation, migration and apoptosis (Paplomata and O’Regan, 2014; Ruchi Sharma et al., 2017). PI3K/AKTsignaling pathway is known to be affected by dysregulated miRNA expression levels (Josse et al., 2014). Here we intended to find miRNA candidate(s) that are involved in the
Author contributions
Z.M., B.M.S., conceived and designed the study and Z.M., ZG and B.M.S. wrote the paper. Z.M., ZG and B.M.S. performed experiments and analyzed the results. P.H provided cancer tissue samples with preparation of pathological features. All authors reviewed the results and approved the final version of the manuscript.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
This study was supported by Tarbiat Modares University and Iran National Science Foundation (INSF) financial aids (Grant Number: 96012144).
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