Construction of miRNA-miRNA networks revealing the complexity of miRNA-mediated mechanisms in trastuzumab treated breast cancer cell lines

Abstract

Trastuzumab is a monoclonal antibody frequently used to prevent the progression of HER2+ breast cancers, which constitute approximately 20% of invasive breast cancers. microRNAs (miRNAs) are small, non-coding RNA molecules that are known to be involved in gene regulation. With their emerging roles in cancer, they are recently promoted as potential candidates to mediate therapeutic actions by targeting genes associated with drug response. In this study we explored miRNA-mediated regulation of trastuzumab mechanisms by identifying the important miRNAs responsible for the drug response via homogenous network analysis. Our network model enabled us to simplify the complexity of miRNA interactions by connecting them through their common pathways. We outlined the functionally relevant miRNAs by constructing pathway-based miRNA-miRNA networks in SKBR3 and BT474 cells, respectively. Identification of the most targeted genes revealed that trastuzumab responsive miRNAs favourably regulate the repression of targets with longer 3’UTR than average considered to be key elements, while the miRNA-miRNA networks highlighted central miRNAs such as hsa-miR-3976 and hsa-miR-3671 that showed strong interactions with the remaining members of the network. Furthermore, the clusters of the miRNA-miRNA networks showed that trastuzumab response was mostly established through cancer related and metabolic pathways. hsa-miR-216b was found to be the part of the most powerful interactions of metabolic pathways, which was defined in the largest clusters in both cell lines. The network based representation of miRNA-miRNA interactions through their shared pathways provided a better understanding of miRNA-mediated drug response and could be suggested for further characterization of miRNA functions.

Clustered miRNAs and their role in biological functions and diseases

“…Yuan et al (2009) showed that intra-cluster co-ordination between miRNAs allows them to target functionally related pathways involving protein-protein interaction networks. Cilek, Ozturk & Gur Dedeoglu (2017) showed that interaction between miR-216b, a member of miR-216 cluster, and miR-3064-3p and miR-32-3p allows them to target similar biological process in breast cancer.…”

“…(Aguda et al, 2008;Brock et al, 2009;Zhu et al, 2014). Similarly, miR-17/92 cluster is overexpressed in cancer with resulting amplification and downregulation of p21 and p27 facilitating cell cycle progression (Perez-Madrigal et al, 2012;Cioffi et al, 2015). miR-545/374a, miR-183/182, miR-106b/25 and miR-221/222 clusters Zhou et al, 2014; all enhance cell proliferation.…”

Potential Regulatory Roles of MicroRNAs and Long Noncoding RNAs in Anticancer Therapies

“…Second, miRNA-miRNA and miRNA-lncRNA networks reveal the complexity of ncRNA-mediated mechanisms in anticancer therapies, providing a better understanding of the ncRNA-mediated drug response and creative research approaches. 98 One outstanding problem is whether ectopic miRNAs and lncRNAs actually function in vivo , and more research utilizing convenient in vivo model systems are needed. Future studies will likely focus on ncRNA-based drug development and integrated clinical trials, which may lead to a cure for cancer.…”

miR-503 suppresses the proliferation and metastasis of esophageal squamous cell carcinoma by triggering autophagy via PKA/mTOR signaling

“…MicroRNAs (miRNAs or miRs) are a subtype of non-coding RNA molecules with functions in post-transcriptional regulation via binding to the 3′-untranslated regions (UTRs) of targeted mRNAs ( 17 , 18 ). The dysregulation of miRNA expression may lead to the destruction of the equilibrium between tumor suppression and promotion ( 19 ).…”