Hsa-miR-3651 could serve as a novel predictor for in-breast recurrence via FRMD3

Abstract

Background MicroRNAs are small non-coding RNAs with pivotal regulatory functions in multiple cellular processes. Their significance as molecular predictors for breast cancer was demonstrated in the past 15 years. The aim of this study was to elucidate the role of hsa-miR-3651 for predicting of local control (LC) in early breast cancer. Results By means of high-throughput technology, hsa-miR-3651 was found to be differentially expressed between patients who experienced local relapse compared to those without (N = 23; p = 0.0035). This result could be validated in an independent cohort of 87 patients using RT-qPCR (p < 0.0005). In a second analysis step with a chip-based microarray containing 70,523 probes of potential target molecules, FERM domain protein 3 (FRMD3) was found to be the most down-regulated protein (N = 21; p = 0.0016). Computational analysis employing different prediction algorithms revealed FRMD3 as a likely downstream target of hsa-miR-3651 with an 8mer binding site between the two molecules. This could be validated in an independent patient set (N = 20, p = 0.134). Conclusion The current study revealed that hsa-miR-3651 is a predictor of LC in early breast cancer via its putative target protein FRMD3. Since microRNAs interfere in multiple pathways, the results of this hypothesis generating study may contribute to the development of tailored therapies for breast cancer in the future.

A Unified Computational Framework for a Robust, Reliable, and Reproducible Identification of Novel miRNAs From the RNA Sequencing Data

“…In comparing with the literature reported miRNA 9 out of 22 (40.90%), 7 out of 8 (87.5%), 10 out of 31 (32.25%), 8 out of 29 (27.58%), 19 out of 34 (55.88%), 12 out of 14 (85.71%), 23 out of 42 (54.76%), and 19 out of 21 (90.47%) miRNAs were found to be reported as dysregulated in the literature of breast cancer. Here, the dysregulated miRNAs identified by miRPipe are found to be reported in multiple breast cancer-related research papers ( Shi Y. et al, 2015 ; Krishnan et al, 2015 ; Hannafon et al, 2016 ; Tan et al, 2016 ; Li et al, 2017 ; Reza et al, 2017 ; Schultz et al, 2017 ; Sripada et al, 2017 ; Xia et al, 2017 ; Chen et al, 2018 ; Lagendijk et al, 2018 ; Lai et al, 2019 ; Li et al, 2019 ; Sun et al, 2019 ; Xie et al, 2019 ; Mahlab-Aviv et al, 2020 ; Zhang et al, 2020 ; Ghafouri-Fard et al, 2021 ; Shen et al, 2021 ; Yang et al, 2021 ; Zellinger et al, 2021 ; Park et al, 2022 ). Only 6 out of 11 (54.54%) miRNAs reported in the original publication of this dataset ( Lin et al, 2021 ) were found to be reported as dysregulated in the literature.…”

Assessing the Role of MicroRNAs in Predicting Breast Cancer Recurrence—A Systematic Review

“…Overall, nineteen studies were included in this systematic review, of which one was a prospective, multicentre clinical trial [ 14 ]. All of the other 18 included studies were of retrospective design [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. A PRISMA flow diagram detailing the systematic search process is outlined in Figure 1 .…”

“…Thirteen studies (68.4%) used a microarray technique to select suitable miRNA for analysis [ 22 , 24 , 26 , 29 , 30 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ], five studies (21.1%) used literature review [ 14 , 23 , 25 , 27 , 31 ], and two studies (10.5%) selected miRNAs from historical lab findings [ 28 , 32 ]. All 19 studies (100%) used quantitative reverse transcription polymerase chain reaction (qRT-PCR) for assessing miRNAs [ 14 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ] ( Table 1 ).…”

FRMD3 inhibits the growth and metastasis of breast cancer through the ubiquitination-mediated degradation of vimentin and subsequent impairment of focal adhesion

“…We preliminarily detected the DNA methylation of the FRMD3 promoter in BRCA cells and MCF10A cells respectively; however, no difference was observed (data not shown). Recently, FRMD3 was found to be the most downregulated protein by hsa-miR-3651, a novel predictor for in-breast recurrence [ 9 ]. Therefore, it may be likely that FRMD3 is downregulated in BRCA through miRNA-mediated silence, but other mechanisms such as gene mutations or lost and the regulation of long non-coding RNA (lncRNA) may also be involved, which should be investigated in future studies.…”

“…As early as 2007, FRMD3 was identified as a tumor suppressor gene in lung cancer, suggesting a potential role in the origin and progression of lung cancer [ 7 ]. Thereafter, high FRMD3 expression was reported to be related to advanced clinicopathological features in rectal cancer patients [ 8 ], and FRMD3 was shown to be the target of Has-miR-3651, a novel predictor for breast cancer recurrence [ 9 ]. However, the functional roles and the underlying mechanisms of FRMD3 in cancers including breast cancer remains largely unknown.…”