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

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 Abbreviations BrCa, breast cancer; ESRP1, Epithelial splicing regulatory protein 1; GEO, Gene Expression Omnibus; GINS1, GINS complex subunit 1; HMGB3, High Mobility Group Box 3; MAGOHB, Mago Homolog B; miRNA, microRNA; RISC, RNA-induced silencing complex; SRPK1, Serine/Arginine-Rich Splicing Factor Kinase 1; TCGA, The Cancer Genome Atlas; TPD52, Tumor Protein D52; VANGL1, Vang-like protein 1.426 Molecular Oncology 14 (2020) 426-446 ª

Circulating miR-99a-5p Expression in Plasma: A Potential Biomarker for Early Diagnosis of Breast Cancer

“…Firstly, we evaluated miR-99a-5p expression in tissue samples from 26 healthy patients and 103 BC patients. The downregulation of miR-99a-5p in BC tissue was confirmed, in agreement with previous studies [ 23 , 24 , 25 , 26 ]. Besides, our result was also validated in the TCGA cohort.…”

“…Several authors assessed miR-99a expression in BC tissues and demonstrated its downregulation when compared to healthy tissues [ 23 , 24 , 25 , 26 ]. In this respect, miR-99a has been confirmed to be a tumour suppressor and its overexpression was associated with proliferation, invasion, and migration inhibition in BC cells in vitro and in vivo [ 23 , 27 ].…”

“…Mir-99a-5p, which functions as a tumour suppressor gene by inhibiting proliferation, migration, and invasion, has been found dysregulated in several tumours [ 21 , 22 ]. Specifically in BC tissues, miR-99a-5p has been consistently reported to be downregulated [ 23 , 24 , 25 , 26 ]. Hence, herein we sought to investigate the applicability of miR-99a-5p expression levels as a minimally invasive BC diagnostic biomarker.…”

FAM64A: A Novel Oncogenic Target of Lung Adenocarcinoma Regulated by Both Strands of miR-99a (miR-99a-5p and miR-99a-3p)

“…We have previously determined miRNA expression signatures in various types of cancers using RNA sequencing [ 15 , 16 , 17 , 18 , 19 ]. Our recent studies have demonstrated that some passenger strands derived from pre-miRNAs contribute to the malignant transformation of cancer cells [ 15 , 16 , 17 , 18 , 19 ].…”

“…We have previously determined miRNA expression signatures in various types of cancers using RNA sequencing [ 15 , 16 , 17 , 18 , 19 ]. Our recent studies have demonstrated that some passenger strands derived from pre-miRNAs contribute to the malignant transformation of cancer cells [ 15 , 16 , 17 , 18 , 19 ]. We have shown that both strands of miRNAs (e.g., pre- miR-144 , pre- miR-145 and pre- miR-150 ) were significantly downregulated in lung cancer tissues, and their ectopic expression attenuated the malignant phenotypes of lung cancer cells (e.g., cancer cell proliferation, migration and invasion) [ 20 , 21 , 22 , 23 , 24 ].…”