miR-5590-3p-YY1 feedback loop promotes the proliferation and migration of triple-negative breast cancer cells.
12 Jun 2019-Journal of Cellular Biochemistry (John Wiley & Sons, Ltd)-Vol. 120, Iss: 10, pp 18415-18424
TL;DR: It can be concluded that miR‐5590‐3p‐YY1 feedback loop promoted the proliferation and migration of TNBC.
Abstract: Lacking of diagnostic and prognostic biomarkers is a significant reason for the poor prognosis of patients with triple-negative breast cancer (TNBC). MicroRNAs (miRNAs) have been discovered to engage in the tumorigenesis and development of TNBC. miR-5590-3p has been found to be involved in the development of gastric cancer, but its role and underlying mechanism in TNBC remain obscure. In this study, it was discovered that miR-5590-3p was downregulated in TNBC tissues and cells. Function assays confirmed that miR-5590-3p overexpression inhibited cell proliferation, migration, and epithelial-mesenchymal transition (EMT) process as well as promoted cell apoptosis in TNBC. Moreover, YY1 could bind with the promoter of miR-5590-3p and overexpression of YY1 inhibited the transcription of miR-5590-3p. It was found that YY1 acted as a downstream target gene to bind with miR-5590-3p and was negatively regulated by miR-5590-3p. Finally, it was discovered that overexpression of YY1 could partially rescue the miR-5590-3p overexpression-mediated inhibitive effect on TNBC progression. Taken together these results, it can be concluded that miR-5590-3p-YY1 feedback loop promoted the proliferation and migration of TNBC.
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TL;DR: This review focuses on the YY1 interacting partners and its target genes in different cancer models, and the possibility of therapeutically targeting the Yy1 in cancers where it functions as a tumor promoter.
Abstract: Yin Yang 1 (YY1), a dual function transcription factor, is known to regulate transcriptional activation and repression of many genes associated with multiple cellular processes including cellular differentiation, DNA repair, autophagy, cell survival vs. apoptosis, and cell division. Owing to its role in processes that upon deregulation are linked to malignant transformation, YY1 has been implicated as a major driver of many cancers. While a large body of evidence supports the role of YY1 as a tumor promoter, recent reports indicated that YY1 also functions as a tumor suppressor. The mechanism by which YY1 brings out opposing outcome in tumor growth vs. suppression is not completely clear and some of the recent reports have provided significant insight into this. Likewise, the mechanism by which YY1 functions both as a transcriptional activator and repressor is not completely clear. It is likely that the proteins with which YY1 interacts might determine its function as an activator or repressor of transcription as well as its role as a tumor suppressor or promoter. Hence, a collection of YY1-protein interactions in the context of different cancers would help us gain an insight into how YY1 promotes or suppresses cancers. This review focuses on the YY1 interacting partners and its target genes in different cancer models. Finally, we discuss the possibility of therapeutically targeting the YY1 in cancers where it functions as a tumor promoter.
103 citations
TL;DR: Recent progress with respect to YY1 and its biological implications in the context of hallmarks of cancer is summarized.
Abstract: Tumorigenesis is a multistep process characterized by the acquisition of genetic and epigenetic alterations. During the course of malignancy development, tumor cells acquire several features that allow them to survive and adapt to the stress-related conditions of the tumor microenvironment. These properties, which are known as hallmarks of cancer, include uncontrolled cell proliferation, metabolic reprogramming, tumor angiogenesis, metastasis, and immune system evasion. Zinc-finger protein Yin Yang 1 (YY1) regulates numerous genes involved in cell death, cell cycle, cellular metabolism, and inflammatory response. YY1 is highly expressed in many cancers, whereby it is associated with cell proliferation, survival, and metabolic reprogramming. Furthermore, recent studies also have demonstrated the important role of YY1-related non-coding RNAs in acquiring cancer-specific characteristics. Therefore, these YY1-related non-coding RNAs are also crucial for YY1-mediated tumorigenesis. Herein, we summarize recent progress with respect to YY1 and its biological implications in the context of hallmarks of cancer.
66 citations
Cites background from "miR-5590-3p-YY1 feedback loop promo..."
...miR-5590-3p Oncogene Repression Breast Tumor cell proliferation, cell death resistance, invasion & metastasis [184]...
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...miR-5590-3p Tumor-suppressor Repression Breast Tumor cell proliferation, cell death resistance, invasion & metastasis [184]...
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TL;DR: MIR100HG promotes the progression of TNBC by sponging miR-5590-3p, thereby upregulating OTX1, suggesting a new potential treatment target for TNBC.
Abstract: As an aggressive subtype of breast cancer with a high risk of recurrence, triple-negative breast cancer (TNBC) lacks available treatment targets. LncRNA MIR100HG promotes cell proliferation in TNBC. However, few studies have investigated the molecular mechanism of MIR100HG in TNBC. Thus, additional in-depth investigations are needed to unravel its associated regulatory mechanism. MIR100HG and miR-5590-3p expression in TNBC tissue samples and cell lines was detected by RT-qPCR. Flow cytometry, transwell, wound-healing, CCK8 and colony formation assays were performed to analyse cell apoptosis, cell cycle, invasion, migration and proliferation. The protein expression of orthodenticle homeobox 1 (OTX1) and proteins in the ERK/MAPK signalling pathway were assessed by western blot analysis. Bioinformatics and luciferase assay were performed to predict and validate the interaction between MIR100HG and miR-5590-3p as well as OTX1 and miR-5590-3p. RNA immunoprecipitation (RIP) was used to detect the interaction between MIR100HG and miR-5590-3p. Subcutaneous tumour growth was observed in nude mice. Immunohistochemistry (IHC) analysis was used to assess OTX1 expression in tumour tissues. MIR100HG expression was upregulated, whereas that of miR-5590-3p was downregulated in TNBC. MIR100HG was shown to directly interact with miR-5590-3p. Furthermore, MIR100HG knockdown could promote TNBC cell apoptosis and cell cycle arrest in G0/G1 phase while inhibiting migration, invasion and proliferation. Furthermore, miR-5590-3p inhibition showed the opposite results and could reverse the effect of MIR100HG knockdown in TNBC cells. MiR-5590-3p downregulated the ERK/MAPK signalling pathway, suppressed the migration, invasion and proliferation of TNBC cells and promoted their apoptosis and cell cycle arrest in G0/G1 phase by targeting OTX1. In addition, MIR100HG knockdown inhibited OTX1 expression by upregulating miR-5590-3p in vivo, thereby inhibiting tumour growth. MIR100HG promotes the progression of TNBC by sponging miR-5590-3p, thereby upregulating OTX1, suggesting a new potential treatment target for TNBC.
22 citations
TL;DR: The most recent findings on the roles of microRNAs (miRNAs) that could potentially be used for miRNA-based therapy in the treatment of breast cancer are summarized and the various therapeutic applications are discussed.
Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that can post-transcriptionally regulate the genes involved in critical cellular processes. The aberrant expressions of oncogenic or tumor suppressor miRNAs have been associated with cancer progression and malignancies. This resulted in the dysregulation of signaling pathways involved in cell proliferation, apoptosis and survival, metastasis, cancer recurrence and chemoresistance. In this review, we will first (i) provide an overview of the miRNA biogenesis pathways, and in vitro and in vivo models for research, (ii) summarize the most recent findings on the roles of microRNAs (miRNAs) that could potentially be used for miRNA-based therapy in the treatment of breast cancer and (iii) discuss the various therapeutic applications.
12 citations
TL;DR: Estimation of the expression of these circulating miRNAs and their association with prognosis in patients with TNBC treated with immunotherapy should be assessed to evaluate their possible use as non-invasive predictive biomarkers.
Abstract: Breast cancer (BC) is the most common type of cancer in women worldwide, and despite advances in treatments, its incidence and mortality are increasing. Therefore, it is necessary to develop new, non-invasive tests that provide more accurate diagnosis and prognosis in a timely manner. A promising approach is measuring the presence of biomarkers to detect tumors at various stages and determine their specific characteristics, thus allowing for more personalized treatment. MicroRNAs (miRNAs) serve a role in gene expression, primarily by interacting with messenger RNAs, and may be potential biomarkers for detecting cancer. They are detectable in tissues and blood, including plasma and/or serum, are stable and often tumor specific. Also, different miRNAs are associated with specific BC molecular subtypes. Triple-negative BC (TNBC) is a type of BC in which the primary targets for hormonal therapy are absent. It is an aggressive phenotype, which frequently metastasizes and is associated with an unfavorable prognosis. The present review focuses on circulating miRNAs in patients with TNBC, with an emphasis on their interaction with the immune response checkpoint genes PD-1, PD-L1 and CTLA4. Modulation and response of the immune system are of interest in cancer treatment due to the success of immunotherapy in the treatment of various neoplasms. Based on the findings of this literature review and the in silico analysis performed as part of this review, it is concluded that circulating hsa-miR-195 and hsa-miR-155 in TNBC interact with checkpoint genes involved in the immune response. Further analysis of the expression of these circulating miRNAs and their association with prognosis in patients with TNBC treated with immunotherapy should be assessed to evaluate their possible use as non-invasive predictive biomarkers. In addition, functional studies to analyze biologically relevant targets in the development and prognosis of TNBC, which could be therapeutic targets, are also recommended.
11 citations
References
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TL;DR: Gen expression profiles from 21 breast cancer data sets and identified 587 TNBC cases may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.
Abstract: Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.
4,215 citations
"miR-5590-3p-YY1 feedback loop promo..." refers background in this paper
...TNBC tumors are always larger and less differentiated and easily metastasize within 5 years of diagnosis in comparison with other breast cancer subtypes.(2,3) TNBC is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER‐2)....
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TL;DR: Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.
Abstract: Purpose: To compare the clinical features, natural history, and outcomes for women with “triple-negative” breast cancer with women with other types of breast cancer. Experimental Design: We studied a cohort of 1,601 patients with breast cancer, diagnosed between January 1987 and December 1997 at Women9s College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor negative, progesterone receptor negative, and HER2neu negative. The prognostic significance of triple-negative breast cancer was explored. Results: The median follow-up time of the 1,601 women was 8.1 years. One hundred and eighty of 1,601 patients (11.2%) had triple-negative breast cancer. Compared with other women with breast cancer, those with triple-negative breast cancer had an increased likelihood of distant recurrence (hazard ratio, 2.6; 95% confidence interval, 2.0-3.5; P P Conclusions: Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.
3,945 citations
"miR-5590-3p-YY1 feedback loop promo..." refers background in this paper
...TNBC tumors are always larger and less differentiated and easily metastasize within 5 years of diagnosis in comparison with other breast cancer subtypes.(2,3) TNBC is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER‐2)....
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TL;DR: The latest scientific information on breast cancer arising in young women is summarized highlighting the heterogeneity and the complex nature of this type of cancer.
Abstract: Despite dramatic advances in cancer research setting, breast cancer remains a major health problem and represents currently a top biomedical research priority. Worldwide, breast cancer is the most common cancer affecting women, and its incidence and mortality rates are expected to increase significantly the next years. Recently the researchers' interest has been attracted by breast cancer arising in young women. Current evidence suggests that in women aged <45 years, breast cancer is unquestionably the leading cause of cancer-related deaths. This type of cancer seems to be highly heterogeneous and has potentially aggressive and complex biological features. However, management strategies, recommendations and options are not age based and the 'complex' biology of this type of cancer remains uncertain and unexplored. In this review, we summarize the latest scientific information on breast cancer arising in young women highlighting the heterogeneity and the complex nature of this type of cancer.
379 citations
"miR-5590-3p-YY1 feedback loop promo..." refers background in this paper
...As an aggressive subtype of breast cancer, triple‐negative breast cancer (TNBC) is the dominant cause of cancer‐ related mortality among women who are younger than 40 years old.(1) TNBC tumors are always larger and less differentiated and easily metastasize within 5 years of diagnosis in comparison with other breast cancer subtypes....
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TL;DR: It is determined that the developmental control of immunoglobulin kappa 3' enhancer (kappa E3') activity is the result of the combined influence of positive- and negative-acting elements.
Abstract: We have determined that the developmental control of immunoglobulin kappa 3' enhancer (kappa E3') activity is the result of the combined influence of positive- and negative-acting elements. We show that a central core in the kappa E3' enhancer is active at the pre-B-cell stage but is repressed by flanking negative-acting elements. The negative-acting sequences repress enhancer activity in a position- and orientation-independent manner at the pre-B-cell stage. We have isolated a human cDNA clone encoding a zinc finger protein (NF-E1) that binds to the negative-acting segment of the kappa E3' enhancer. This protein also binds to the immunoglobulin heavy-chain enhancer mu E1 site. NF-E1 is encoded by the same gene as the YY-1 protein, which binds to the adeno-associated virus P5 promoter. NF-E1 is also the human homologue of the mouse delta protein, which binds to ribosomal protein gene promoters. The predicted amino acid sequence of this protein contains features characteristic of transcriptional activators as well as transcriptional repressors. Cotransfection studies with this cDNA indicate that it can repress basal promoter activity. The apparent dual function of this protein is discussed.
309 citations
"miR-5590-3p-YY1 feedback loop promo..." refers background in this paper
...Yin Yang‐1 (YY1) is a zinc finger transcription factor that ubiquitously expressed in many tissues.(21) YY1 is well‐known for its role in transcription regulation, which means it can regulate gene transcription to promote the development and progression of human cancers....
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TL;DR: Various ways to target transcription factors in cancer models are discussed: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment.
Abstract: Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions.
233 citations
"miR-5590-3p-YY1 feedback loop promo..." refers background in this paper
...Transcription factors are proteins that can activate or inhibit the transcription of genes, playing a significant role in various cancers.(19) For instance, transcription factor Sp1 has a carcinogenic effect in pancreatic cancer....
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