RNA-sequence-based microRNA expression signature in breast cancer: tumor-suppressive miR-101-5p regulates molecular pathogenesis.

Hiroko Toda,Shogo Moriya,Shoji Natsugoe,Tetsuya Idichi,Yasutaka Yamada,Yuko Kijima,Kosei Maemura,Takaaki Fujii,Nijiro Nohata,Sasagu Kurozumi,Naohiko Seki,Jun Horiguchi,Yoshiaki Shinden

doi:10.1002/1878-0261.12602

Abstract

Aberrantly expressed microRNA (miRNA) are known to disrupt intracellular RNA networks in cancer cells. Exploring miRNA‐dependent molecular networks is a major challenge in cancer research. In this study, we performed RNA‐sequencing of breast cancer (BrCa) clinical specimens to identify tumor‐suppressive miRNA in BrCa. In total, 64 miRNA were identified as candidate tumor‐suppressive miRNA in BrCa cells. Analysis of our BrCa signature revealed that several miRNA duplexes (guide strand/passenger strand) derived from pre‐miRNA were downregulated in BrCa tissues (e.g. miR‐99a‐5p/‐3p, miR‐101‐5p/‐3p, miR‐126‐5p/‐3p, miR‐143‐5p/‐3p, and miR‐144‐5p/‐3p). Among these miRNA, we focused on miR‐101‐5p, the passenger strand of pre‐miR‐101, and investigated its tumor‐suppressive roles and oncogenic targets in BrCa cells. Low expression of miR‐101‐5p predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0316). Ectopic expression of miR‐101‐5p attenuated aggressive phenotypes, e.g. proliferation, migration, and invasion, in BrCa cells. Finally, we identified seven putative oncogenic genes (i.e. High Mobility Group Box 3, Epithelial splicing regulatory protein 1, GINS complex subunit 1 (GINS1), Tumor Protein D52, Serine/Arginine‐Rich Splicing Factor Kinase 1, Vang‐like protein 1, and Mago Homolog B) regulated by miR‐101‐5p in BrCa cells. The expression of these target genes was associated with the molecular pathogenesis of BrCa. Furthermore, we explored the oncogenic roles of GINS1, whose function had not been previously elucidated, in BrCa cells. Aberrant expression of GINS1 mRNA and protein was observed in BrCa clinical specimens, and high GINS1 expression significantly predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0126). Knockdown of GINS1 inhibited the malignant features of BrCa cells. Thus, identification of tumor‐suppressive miRNA and molecular networks controlled by these miRNA in BrCa cells may be an effective strategy for elucidation of the molecular pathogenesis of this disease.

Highlights

Breast cancer (BrCa) is the most common malignancy among women, and ~ 2 million cases are newly diagnosed each year, resulting in more than 620 000 deaths annually (Bray et al, 2018; Ferlay et al, 2015)
We focused on GINS complex subunit 1 (GINS1) and showed that its aberrant expression was closely related to BrCa malignant phenotypes
Our signature revealed that several novel miRNA, including passenger strands of miRNA, were downregulated in BrCa tissues

Summary

Introduction

Breast cancer (BrCa) is the most common malignancy among women, and ~ 2 million cases are newly diagnosed each year, resulting in more than 620 000 deaths annually (Bray et al, 2018; Ferlay et al, 2015). Based on gene expression signature analysis, BrCa can be classified into intrinsic molecular subtypes (Perou et al, 2000; Sotiriou et al, 2003). According to the 12th St Gallen International Breast Cancer Conference, BrCa can be classified into the following five subtypes, which can facilitate the selection of treatment strategies: luminal-A, luminal-B [human epidermal growth factor receptor 2 (HER2)-positive], luminal-B (HER2-negative), HER2-positive, and triple negative (Goldhirsch et al, 2011). These intrinsic molecular subtypes are related to the biological features of BrCa and are essential for treatment selection

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