scholarly journals Unearthing Regulatory Axes of Breast Cancer circRNAs Networks to Find Novel Targets and Fathom Pivotal Mechanisms

2019 ◽  
Author(s):  
Farzaneh Afzali ◽  
Mahdieh Salimi
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Elements ◽  
Point Of View ◽  
Circular Rnas ◽  
Biological Processes ◽  
Ppi Network ◽  
Luminal A

ABSTRACTCircular RNAs (circRNAs) along other complementary regulatory elements in ceRNAs networks possess valuable characteristics for both diagnosis and treatment of several human cancers including breast cancer (BC). In this study, we combined several systems biology tools and approaches to identify influential BC circRNAs, RNA binding proteins (RBPs), miRNAs, and related mRNAs to study and decipher the BC triggering biological processes and pathways.Rooting from the identified total of 25 co-differentially expressed circRNAs (DECs) between triple negative (TN) and luminal A subtypes of BC from microarray analysis, five hub DECs (hsa_circ_0003227, hsa_circ_0001955, hsa_circ_0020080, hsa_circ_0001666, and hsa_circ_0065173) and top eleven RBPs (AGO1, AGO2, EIF4A3, FMRP, HuR (ELAVL1), IGF2BP1, IGF2BP2, IGF2BP3, EWSR1, FUS, and PTB) were explored to form the upper stream regulatory elements. All the hub circRNAs were regarded as super sponge having multiple miRNA response elements (MREs) for numerous miRNAs. Then four leading miRNAs (hsa-miR-149, hsa-miR-182, hsa-miR-383, and hsa-miR-873) accountable for BC progression were also introduced from merging several ceRNAs networks. The predicted 7- and 8-mer MREs matches between hub circRNAs and leading miRNAs ensured their enduring regulatory capability. The mined downstream mRNAs of the circRNAs-miRNAs network then were presented to STRING database to form the PPI network and deciphering the issue from another point of view. The BC interconnected enriched pathways and processes guarantee the merits of the ceRNAs networks’ members as targetable therapeutic elements.This study suggested extensive panels of novel covering therapeutic targets that are in charge of BC progression in every aspect, hence their impressive role cannot be excluded and needs deeper empirical laboratory designs.

scholarly journals RBPsuite: RNA-protein binding sites prediction suite based on deep learning

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaoyong Pan ◽  
Yi Fang ◽  
Xianfeng Li ◽  
Yang Yang ◽  
Hong-Bin Shen
Keyword(s):  
Deep Learning ◽  
Binding Sites ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Circular Rnas ◽  
Biological Processes ◽  
Learning Models ◽  
Protein Binding Sites ◽  
Full Length Sequence ◽  
Computationally Intensive

Abstract Background RNA-binding proteins (RBPs) play crucial roles in various biological processes. Deep learning-based methods have been demonstrated powerful on predicting RBP sites on RNAs. However, the training of deep learning models is very time-intensive and computationally intensive. Results Here we present a deep learning-based RBPsuite, an easy-to-use webserver for predicting RBP binding sites on linear and circular RNAs. For linear RNAs, RBPsuite predicts the RBP binding scores with them using our updated iDeepS. For circular RNAs (circRNAs), RBPsuite predicts the RBP binding scores with them using our developed CRIP. RBPsuite first breaks the input RNA sequence into segments of 101 nucleotides and scores the interaction between the segments and the RBPs. RBPsuite further detects the verified motifs on the binding segments gives the binding scores distribution along the full-length sequence. Conclusions RBPsuite is an easy-to-use online webserver for predicting RBP binding sites and freely available at http://www.csbio.sjtu.edu.cn/bioinf/RBPsuite/.

scholarly journals Identification of long non-coding RNAs and RNA binding proteins in breast cancer subtypes

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Claudia Cava ◽  
Alexandros Armaos ◽  
Benjamin Lang ◽  
Gian G. Tartaglia ◽  
Isabella Castiglioni
Keyword(s):  
Breast Cancer ◽  
Binding Proteins ◽  
Rna Binding ◽  
Molecular Subtypes ◽  
Rna Binding Proteins ◽  
Breast Cancer Subtypes ◽  
Luminal A ◽  
Cancer Subtypes ◽  
Luminal B ◽  
Non Coding Rnas

AbstractBreast cancer is a heterogeneous disease classified into four main subtypes with different clinical outcomes, such as patient survival, prognosis, and relapse. Current genetic tests for the differential diagnosis of BC subtypes showed a poor reproducibility. Therefore, an early and correct diagnosis of molecular subtypes is one of the challenges in the clinic. In the present study, we identified differentially expressed genes, long non-coding RNAs and RNA binding proteins for each BC subtype from a public dataset applying bioinformatics algorithms. In addition, we investigated their interactions and we proposed interacting biomarkers as potential signature specific for each BC subtype. We found a network of only 2 RBPs (RBM20 and PCDH20) and 2 genes (HOXB3 and RASSF7) for luminal A, a network of 21 RBPs and 53 genes for luminal B, a HER2-specific network of 14 RBPs and 30 genes, and a network of 54 RBPs and 302 genes for basal BC. We validated the signature considering their expression levels on an independent dataset evaluating their ability to classify the different molecular subtypes with a machine learning approach. Overall, we achieved good performances of classification with an accuracy >0.80. In addition, we found some interesting novel prognostic biomarkers such as RASSF7 for luminal A, DCTPP1 for luminal B, DHRS11, KLC3, NAGS, and TMEM98 for HER2, and ABHD14A and ADSSL1 for basal. The findings could provide preliminary evidence to identify putative new prognostic biomarkers and therapeutic targets for individual breast cancer subtypes.

scholarly journals Bioinformatics for differential proteomics data between triple-negative breast cancer and luminal A subtype breast cancer

2020 ◽  
Author(s):  
guogang wu ◽  
Lei Zhang ◽  
Chunyan Liang ◽  
Yao Cheng ◽  
Chenguang Lv ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Synthesis ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Translation Initiation Factor ◽  
Osteosarcoma Cell ◽  
Biological Processes ◽  
Luminal A ◽  
Differential Proteomics ◽  
Rna Damage

Abstract Background The heterogeneity between different subtypes of breast cancer has been established. Triple-negative breast cancer (TNBC) is the type of breast cancer with the highest recurrence rate, metastasis rate, and worst prognosis, while luminal A breast cancer is the subtype with the best prognosis. To study the heterogeneity of the two subtypes of breast cancer is important. Methods We adopted a quantitative proteomics detection method based on data-independent acquisition and screened all differentially proteins between TNBC and luminal A breast cancer. Ingenuity Pathways Analysis was used for analysis. Results We found that 207 proteins were up-regulated and 326 proteins were down-regulated. Classical pathway analysis showed that Eukaryotic translation initiation factor 2 (EIF2) signaling was significantly activated, in which EIF2α and other molecules were significantly up-regulated. The upstream regulatory analysis predicted 18 strong activators and 63 strong inhibitors, among which v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) was the strongest activator and tretinoin was the strongest inhibitor. Based on disease and function analysis, it was found that differentially proteins were enriched in 41 biological processes, with RNA damage and repair and protein synthesis the most significant biological processes. There were 14 diseases or functions that were significantly activated and 35 that were significantly suppressed. Among the diseases or functions, the differentially proteins had the most significant inhibitory effect on osteosarcoma cell death. According to an analysis of the interaction network, 25 molecular interaction networks were found and the network with the highest score mainly affected the diseases and functions of cancer, protein synthesis, and RNA damage and repair. Conclusion We identified many key proteins with TNBC heterogeneous characteristics and differentially expression, which will provide an abundance of new information for screening TNBC therapeutic specific targets and biomarkers.

scholarly journals Knockdown of Musashi RNA Binding Proteins Decreases Radioresistance but Enhances Cell Motility and Invasion in Triple-Negative Breast Cancer

2020 ◽  
Vol 21 (6) ◽  
pp. 2169
Author(s):  
Fabian M. Troschel ◽  
Annemarie Minte ◽  
Yahia Mahmoud Ismail ◽  
Amr Kamal ◽  
Mahmoud Salah Abdullah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Invasion ◽  
Cell Cycle Progression ◽  
Triple Negative ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Notch Pathway ◽  
Cycle Progression ◽  
Invasion And Migration ◽  
And Migration

The therapeutic potential of Musashi (MSI) RNA-binding proteins, important stemness-associated gene expression regulators, remains insufficiently understood in breast cancer. This study identifies the interplay between MSI protein expression, stem cell characteristics, radioresistance, cell invasiveness and migration. MSI-1, MSI-2 and Notch pathway elements were investigated via quantitative polymerase chain reaction (qPCR) in 19 triple-negative breast cancer samples. Measurements were repeated in MDA-MB-231 cells after MSI-1 and -2 siRNA-mediated double knockdown, with further experiments performed after MSI silencing. Flow cytometry helped quantify expression of CD44 and leukemia inhibitory factor receptor (LIFR), changes in apoptosis and cell cycle progression. Proliferation and irradiation-induced effects were assessed using colony formation assays. Radiation-related proteins were investigated via Western blots. Finally, cell invasion assays and digital holographic microscopy for cell migration were performed. MSI proteins showed strong correlations with Notch pathway elements. MSI knockdown resulted in reduction of stem cell marker expression, cell cycle progression and proliferation, while increasing apoptosis. Cells were radiosensitized as radioresistance-conferring proteins were downregulated. However, MSI-silencing-mediated LIFR downregulation resulted in enhanced cell invasion and migration. We conclude that, while MSI knockdown results in several therapeutically desirable consequences, enhanced invasion and migration need to be counteracted before knockdown advantages can be fully exploited.

scholarly journals Altered RNA splicing initiates the viral mimicry response from inverted SINEs following type I PRMT inhibition in Triple-Negative Breast Cancer

2021 ◽  
Author(s):  
Cheryl Arrowsmith ◽  
Qin Wu ◽  
David Nie ◽  
Wail alawi ◽  
Jennifer Cruickshank ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Breast Cancer Subtype ◽  
Arginine Methylation ◽  
Interferon Response ◽  
Type I

Abstract Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here, we undertook a screen of epigenetic chemical probes to systematically uncover the epigenetic regulators critical for TNBC growth. We identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), as having anti-tumor growth activity in TNBC in vitro and in vivo. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses pre- and post-MS023 treatment is a functional biomarker and determinant of response; and these observations extend to a panel of patient-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA (dsRNA). The observed dsRNA accumulation is derived, at least in part, from inverted-repeat Alus (IR-Alus), many of which are expressed from retained introns induced by MS023, which inhibits arginine methylation of RNA-binding proteins and alters mRNA splicing machinery. Together, our results represent a shift in understanding the anti-tumor mechanism of type I PRMT inhibitors and provide a novel rationale and biomarker approach for the clinical development of type I PRMT inhibitors.

scholarly journals MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Fengxia Chen ◽  
Qingqing Wang ◽  
Xiaoyan Yu ◽  
Ningning Yang ◽  
Yuan Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Alternative Splicing ◽  
Cyclin D1 ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Negative Regulator ◽  
Breast Epithelial Cell

AbstractTriple-negative breast cancer (TNBC) is the most aggressive subtype with the worst prognosis and the highest metastatic and recurrence potential, which represents 15–20% of all breast cancers in Chinese females, and the 5-year overall survival rate is about 80% in Chinese women. Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. Here, we showed that MCPIP1 was downregulated in 80 TNBC tissues and five TNBC cell lines compared to adjacent paracancerous tissues and one human immortalized breast epithelial cell line, while its high expression levels were associated with increased overall survival in TNBC patients. We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells. Subsequently, we showed that CTF5 participated in MCPIP1-mediated antiproliferative effect by transcriptionally repressing cyclin D1 expression, as well as downregulating its downstream signaling targets p-Rb and E2F1. Conclusively, our findings provided novel insights into the anti-oncogenic mechanism of MCPIP1, suggesting that MCPIP1 could serve as an alternative treatment target in TNBC.

scholarly journals Inflammatory Breast Cancer: Clinical Characteristics and Influence of Molecular Subtypes on Treatment Response

2021 ◽  
Vol 107 (1_suppl) ◽  
pp. 12-12
Author(s):  
D Aissaoui ◽  
M Bohli ◽  
R Ben Amor ◽  
J Yahyaoui ◽  
A Hamdoun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Response ◽  
Inflammatory Breast Cancer ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Luminal A ◽  
Her2 Positive ◽  
Luminal B ◽  
Significant Difference

Introduction: Inflammatory Breast Cancer (IBC) is a rare and very aggressive breast cancer with poor prognosis. The prevalence is different from a country to another. In Tunisia, it is about 5 to 7% of breast cancer. The aim of this study is to describe the epidemiological and histopathological features of patients with inflammatory breast cancer and to evaluate the treatment response according to the molecular subtypes. Methods: This retrospective review identified 31 patients with no metastatic IBC treated in our radiotherapy department between December 2019 and November 2020. IBC was confirmed using the clinical criteria. Baseline clinic-pathological and treatment information was retrieved from medical records. Statistical analysis was performed with IBM SPSS V.20. Results: Median age was 51.3 years [27-68]. 48% of tumors were grade 3. The average tumor size was 36mm [10-90]. The histological type was ductal carcinoma in 97%. Vascular invasion was noted in 24 patients (77%). Thirty patients were classified as stage IIIB and one patient was IIIC. 74% were hormone receptor positive and 45% were HER2 positive. Luminal B was the predominant subtype (52%) followed by Her2 positive (32%), Luminal A (23%), and triple negative (3%) All patients had chemotherapy: neoadjuvant for 26 patients (84%) and adjuvant for 5 patients (16%). Nine patients (29%) had tumor pathological complete response (pCR). Partial response was observed in 18 patients (58%). Lymph node pCR was noted in 16% of cases (n=5). Endocrine therapy and trastuzumab were given to 76% and 45% of patients, respectively. The influence of the molecular subtype was not statistically significant on the response to neoadjuvant treatment. The highest rate of pCR were 43% for Her2positive, then 27%, 21% and 9% for Luminal B, Luminal A and Triple negative, respectively (p=0.2). Conclusion: Our study showed a high percentage of hormone receptor and Her2+ (74% and 45% respectively) in IBC. Luminal B was the most frequent subtype. Anthracycline-based chemotherapy and trastuzumab improved the pCR rate: 44% for Her2positive. Triple negative showed poorer pCR than other breast cancer subtype without a significant difference. A larger study is warranted to confirm our findings.

scholarly journals Iterative Variable Selection for High-Dimensional Data: Prediction of Pathological Response in Triple-Negative Breast Cancer

Mathematics ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 222
Author(s):  
Juan C. Laria ◽  
M. Carmen Aguilera-Morillo ◽  
Enrique Álvarez ◽  
Rosa E. Lillo ◽  
Sara López-Taruella ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Variable Selection ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
A Priori ◽  
Simulated Data ◽  
Point Of View ◽  
High Dimensional ◽  
Whole Genome ◽  
Genome Context

Over the last decade, regularized regression methods have offered alternatives for performing multi-marker analysis and feature selection in a whole genome context. The process of defining a list of genes that will characterize an expression profile remains unclear. It currently relies upon advanced statistics and can use an agnostic point of view or include some a priori knowledge, but overfitting remains a problem. This paper introduces a methodology to deal with the variable selection and model estimation problems in the high-dimensional set-up, which can be particularly useful in the whole genome context. Results are validated using simulated data and a real dataset from a triple-negative breast cancer study.

scholarly journals CircWAC induces chemotherapeutic resistance in triple-negative breast cancer by targeting miR-142, upregulating WWP1 and activating the PI3K/AKT pathway

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Lei Wang ◽  
Yehui Zhou ◽  
Liang Jiang ◽  
Linlin Lu ◽  
Tiantian Dai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Circular Rnas ◽  
Chemotherapeutic Resistance ◽  
Repressive Effect

Abstract Background Chemotherapeutic resistance is the main cause of clinical treatment failure and poor prognosis in triple-negative breast cancer (TNBC). There is no research on chemotherapeutic resistance in TNBC from the perspective of circular RNAs (circRNAs). Methods TNBC-related circRNAs were identified based on the GSE101124 dataset. Quantitative reverse transcription PCR was used to detect the expression level of circWAC in TNBC cells and tissues. Then, in vitro and in vivo functional experiments were performed to evaluate the effects of circWAC in TNBC. Results CircWAC was highly expressed in TNBC and was associated with worse TNBC patient prognosis. Subsequently, it was verified that downregulation of circWAC can increase the sensitivity of TNBC cells to paclitaxel (PTX) in vitro and in vivo. The expression of miR-142 was negatively correlated with circWAC in TNBC. The interaction between circWAC and miR-142 in TNBC cells was confirmed by RNA immunoprecipitation assays, luciferase reporter assays, pulldown assays, and fluorescence in situ hybridization. Mechanistically, circWAC acted as a miR-142 sponge to relieve the repressive effect of miR-142 on its target WWP1. In addition, the overall survival of TNBC patients with high expression of miR-142 was significantly better than that of patients with low expression of miR-142, and these results were verified in public databases. MiR-142 regulated the expression of WWP1 and the activity of the PI3K/AKT pathway. It was confirmed that WWP1 is highly expressed in TNBC and that the prognosis of patients with high WWP1 expression is poor. Conclusions CircWAC/miR-142/WWP1 form a competing endogenous RNA (ceRNA) network to regulate PI3K/AKT signaling activity in TNBC cells and affect the chemosensitivity of cells.

scholarly journals RNA m6A modification orchestrates a LINE-1–host interaction that facilitates retrotransposition and contributes to long gene vulnerability

Cell Research ◽  
2021 ◽  
Author(s):  
Feng Xiong ◽  
Ruoyu Wang ◽  
Joo-Hyung Lee ◽  
Shenglan Li ◽  
Shin-Fu Chen ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Elements ◽  
Host Interaction ◽  
Damage Repair ◽  
Novel Host ◽  
Cell Type Specific ◽  
Human Fetal Tissues ◽  
Long Genes

AbstractThe molecular basis underlying the interaction between retrotransposable elements (RTEs) and the human genome remains poorly understood. Here, we profiled N6-methyladenosine (m6A) deposition on nascent RNAs in human cells by developing a new method MINT-Seq, which revealed that many classes of RTE RNAs, particularly intronic LINE-1s (L1s), are strongly methylated. These m6A-marked intronic L1s (MILs) are evolutionarily young, sense-oriented to hosting genes, and are bound by a dozen RNA binding proteins (RBPs) that are putative novel readers of m6A-modified RNAs, including a nuclear matrix protein SAFB. Notably, m6A positively controls the expression of both autonomous L1s and co-transcribed L1 relics, promoting L1 retrotransposition. We showed that MILs preferentially reside in long genes with critical roles in DNA damage repair and sometimes in L1 suppression per se, where they act as transcriptional “roadblocks” to impede the hosting gene expression, revealing a novel host-weakening strategy by the L1s. In counteraction, the host uses the SAFB reader complex to bind m6A-L1s to reduce their levels, and to safeguard hosting gene transcription. Remarkably, our analysis identified thousands of MILs in multiple human fetal tissues, enlisting them as a novel category of cell-type-specific regulatory elements that often compromise transcription of long genes and confer their vulnerability in neurodevelopmental disorders. We propose that this m6A-orchestrated L1–host interaction plays widespread roles in gene regulation, genome integrity, human development and diseases.

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