Pathology - Research and Practice 251 (2023) 154850
Available online 5 October 2023
0344-0338/© 2023 Elsevier GmbH. All rights reserved.
Review
The complex role of MEG3: An emerging long non-coding RNA in breast cancer
Md Sadique Hussain
a, Abdullah A. Majami
b, Haider Ali
c,*, Gaurav Gupta
d,e,f, Waleed Hassan Almalki
g, Sami I. Alzarea
h, Imran Kazmi
b, Rahamat Unissa Syed
i,j, Nasrin E. Khalifa
i,j,k, Mohammed Khaled Bin Break
j,l, Ruqaiyah Khan
m, Najla Altwaijry
n, Rahul Sharma
aaSchool of Pharmaceutical Sciences, Jaipur National University, Jagatpura, 302017, Jaipur, Rajasthan, India
bDepartment of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
cDepartment of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan
dCentre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
eSchool of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
fSchool of Pharmacy, Suresh Gyan Vihar University, Jagatpura, 302017, Jaipur, India
gDepartment of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
hDepartment of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
iDepartment of Pharmaceutics, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia
jMedical and Diagnostic Research Centre, University of Hail, Hail 55473, Saudi Arabia
kDepartment of Pharmaceutics, Faculty of Pharmacy, University of Khartoum, 11115, Sudan
lDepartment of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia
mDepartment of Basic Health Sciences, Deanship of Preparatory Year for the Health Colleges, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
nDepartment of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint, Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
A R T I C L E I N F O Keywords:
MEG3 Breast cancer Long non-coding RNA miRNAs
A B S T R A C T
MEG3, a significant long non-coding RNA (lncRNA), substantially functions in diverse biological processes, particularly breast cancer (BC) development. Within the imprinting DLK-MEG3 region on human chromosomal region 14q32.3, MEG3 spans 35 kb and encompasses ten exons. It exerts regulatory effects through intricate interactions with miRNAs, proteins, and epigenetic modifications. MEG3’s multifaceted function in BC is evident in gene expression modulation, osteogenic tissue differentiation, and involvement in bone-related conditions. Its role as a tumor suppressor is highlighted by its influence on miR-182 and miRNA-29 expression in BC. Addi- tionally, MEG3 is implicated in acute myocardial infarction and endothelial cell function, emphasising cell- specific regulatory mechanisms. MEG3’s impact on gene activity encompasses transcriptional and post- translational adjustments, including DNA methylation, histone modifications, and interactions with transcrip- tion factors. MEG3 dysregulation is linked to unfavourable outcomes and drug resistance. Notably, higher MEG3 expression is associated with enhanced survival in BC patients. Overcoming challenges such as unravelling context-specific interactions, understanding epigenetic control, and translating findings into clinical applications is imperative. Prospective endeavours involve elucidating underlying mechanisms, exploring epigenetic alter- ations, and advancing MEG3-based diagnostic and therapeutic approaches. A comprehensive investigation into broader signaling networks and rigorous clinical trials are pivotal. Rigorous validation through functional and molecular analyses will shed light on MEG3’s intricate contribution to BC progression.
* Corresponding author.
E-mail addresses: [email protected], [email protected] (H. Ali).
Contents lists available at ScienceDirect
Pathology - Research and Practice
journal homepage: www.elsevier.com/locate/prp
https://doi.org/10.1016/j.prp.2023.154850
Received 22 August 2023; Received in revised form 24 September 2023; Accepted 2 October 2023
monary microvascular endothelial cells (HPMECs) and bronchial epithelial cells (HBECs) [5]. Furthermore, MEG3 has a role in the growth of breast cancers (BCs) by acting as a tumor suppressor by modulating the gene expression of miR-182 and miRNA-29 [6]. MEG3 is also linked to acute myocardial infarction (AMI), with a higher degree of activity in plasma in individuals with AMI than in non-AMI [7]. MEG3 additionally communicates with EZH2 to control integrin signaling and the func- tioning of endothelial cells (ECs) [8]. MEG3 also regulates the DNA damaging reaction (DDR) in ECs via the p53 network, which is a primary integrator of the DDR-induced apoptosis and cell growth [9]. MEG3 plays a variety of biological functions and is implicated in a variety of illnesses and disorders. MEG3 has been studied in various cell types, such as cancerous cells, neurons, hepatocytes, cardiac fibroblasts, and ECs [10–15]. MEG3 has recently been revealed to be altered in a variety of cancerous tissues and cell lines [16,17]. Moreover, a recent study demonstrated that MEG3 levels were considerably lower in BC tissues than in BC individuals’ healthy breast tissues. Reduced MEG3 levels were an independently negative prognosis marker for individuals with BC [18]. Even though MEG3 has been widely investigated in various types of tumors, its influence on BC has only recently been discovered, and the molecular mechanisms that regulate MEG3 modulation of BC remain mainly unknown [19,20]. MEG3 modulates p53 signaling on a cell-by-cell mechanism. In cancerous cells and neurons, MEG3 engages with p53 to trigger p53-mediated suppression of cell growth and acti- vation of apoptosis [10,12,13]. MEG3, on the other hand, engages with p53 in cardiac fibroblasts but does not influence p53 reaction, cell death, or development [11]. These findings suggest that MEG3 regulates p53 signaling in a cell-specific way.
MEG3 may influence targeted gene activity via translation, tran- scription, post-translational changes, and epigenetic influence.
Improper functioning of MEG3 has been associated with poor outcomes and drug resistance (DR) in investigations. MEG3 may influence its target genes via transcriptional and post-translational mechanisms.
MEG3, for example, may enhance the levels of p53 by increasing tran- scriptional activities and post-translational alterations [21]. MEG3 in- hibition was related to the nickel-induced promotion of hypermethylation via increased DNMT3b levels, whilst PHLPP1 tran- scriptional suppression was linked to MEG3’s decreased interaction with its suppressive transcription partner c-Jun [9].
lncRNAs have been discovered to substantially impact the biology of tumors, especially cancer growth and development, by functioning as tumor drivers or inhibitors [22–24]. lncRNA instability has been asso- ciated with various cancers, notably triple-negative BCs (TNBCs), ovarian, lung, and pancreatic cancer [25–28]. Several biological func- tions can be regulated by LncRNAs, such as epigenetic alterations, cell division, growth, division, movement, and death. Furthermore, lncRNAs can engage in various signaling systems, such as the Hippo signaling system, which is important in cancer-associated circuits [22].
The overview of the study is presumably intended to thoroughly investigate and examine the many aspects of MEG3’s contribution to BCs. MEG3 has piqued the curiosity of researchers because of its possible role in BC formation and progress as a lncRNA. The present review aims
less, it is crucial to highlight that these trials focused on a specific group and subtype of BCs. More studies will be required to understand MEG3’s function in BCs completely. Tumor spatial profiling with the GeoMx Digital Spatial Profiler (DSP) allows investigators to define the genomic variety in the BCs TME, which can provide light on the biological mechanisms of tumor development comprehensively [32]. Table 1 summarizes the involvement of MEG3 in BC investigations.
2.2. Epigenetic mechanisms regulating MEG3 expression
Epigenetic processes are important in modulating the regulation of genes, notably MEG3 activity. MEG3 expression is influenced by several variables, including DNA methylation, cyclic adenosine monophosphate (CAMP), and nuclear factor-κB (NF-κB). MEG3 can control the targeted genes both transcriptionally and post-translationally. MEG3, for instance, can increase the expression of p53 by increasing transcription and post-translational alterations. MEG3 may communicate with the histone H3K27 methyltransferase EZH2 to control integrin signaling and the functioning of ECs directly [4,21,33–35]. Furthermore, increased MEG3 activity has been linked to impaired EC function in human um- bilical vein ECs (HUVECs) of children in vitro fertilization (IVF) via epigenetic modulation. MEG3 foster hypomethylation is caused by increased MEG3 transcription. As a result, MEG3 genomic regulation offers a possible strategy for mitigating the increased likelihood of hy- pertension in IVF children [36,37]. Nevertheless, More study is required to comprehend the epigenetic processes that regulate MEG3 expression thoroughly.
2.2.1. DNA methylation
DNA methylation is adding methyl to DNA, which can alter how genes are expressed. Multiple researches have been conducted to eval- uate the association between MEG3 methylation of the DNA and numerous health consequences. One study discovered that paternal nonoccupational contact with arsenic alters the DNA methylation state of MEG3 in sperm from individuals’ DNA [38]. Another investigation found that prenatal connection with lead changes DNA methylation of imprinted genes such as MEG3, leading to decreased birth weight and accelerated maturation [39]. Furthermore, research in cattle models discovered that the amount of methylation in the imprinting genes APEG3, MEG3, and MEG9 was lower in non-triggered oocytes in contrast to activated oocytes [40]. Furthermore, aberrant MEG3 methylation has been identified as a possible indicator of cervical cancer [41,42]. Overall, these results imply that MEG3 DNA methylation may influence various medical conditions and deserves to be studied extensively.
2.2.2. Histone modifications
There is no direct information on MEG3 histone alterations.
Numerous research studies have looked at the link between histone remodelling and genes’ activity in general. Histone changes are post- translational alterations that can have a biochemical impact on DNA- templated activities [43,44]. They can be implanted due to
DNA-templated procedures to reaffirm and record the occurrence, or they may serve a causal (or instructional) part in DNA-templated events [43]. Histone alterations store and transmit complex messages regarding the status of the genomes, and they can influence host activity [45].
Generally, histone changes are carried out by enzymes that operate on the N-terminal ends of histones, utilizing amino acids [46]. Acetylation, methylation, phosphorylation, and ubiquitination are all examples of histone alterations [46,47]. These changes can affect the design and operation of chromatin, enabling the shift from normal chromatin be- liefs to ones that occur in a state of harm to DNA [44].
There is no direct information on MEG3 histone alterations. Ac- cording to one research, MEG3 is dramatically reduced in pancreatic neuroendocrine tumors (PNETs), and MEG3 loss correlates with abnormal overexpression of the carcinogenic hepatocyte growth factor (HGF) receptor c-MET in PNETs. The research found MEG3 interacting with specific genomic areas surrounding the c-Met gene using chromatin separation by RNA extraction and sequencing. These c-Met areas exhibited unique enhancer-signature histone alterations in their lack of MEG3 [48] (Table 1).
3. Interaction with transcription factors and RNA-binding proteins
MEG3 has been discovered to engage with numerous transcription variables and RNA-binding molecules in diverse situations. It has been demonstrated to alter the TLR3 signaling cascade in cells with prostate
cancer [52]. MEG3 conflicts with microRNA-21 in psoriasis vulgaris, regulating cell growth and apoptotic ratio [53]. MEG3 binds with the dyskeratosis congenita 1 (DKC1) molecule in lung cancer, inhibiting the growth of cells, movement, spread, and telomerase function [54].
MEG3–205 enhances kidney fibrosis and inflammation in diabetic ne- phropathy by influencing MyD88 expression [55]. DNMT1 inhibits MEG3 activity in breast cancer by elevating MEG3 methylation [31].
Lastly, the transcription component TP63 promotes KRT17 expression and triggers epithelial-mesenchymal transition (EMT) in thyroid carci- noma [56]. The results presented imply that MEG3 participates in various biological functions and links with multiple transcription vari- ables and RNA-binding proteins to influence the expression of genes.
4. Tumor suppressor role of MEG3 in breast cancer 4.1. Inhibition of cell proliferation and growth
MEG3 has been discovered to decrease the proliferation of cells as well as the development of BCs (Fig. 2) [49]. Based on research, MEG3 is decreased in TNBCs and is negatively associated with the levels of MCM3AP-AS1, a carcinogenic lncRNA. MCM3AP-AS1 overexpression decreased MEG3 expression, but MEG3 overexpression did not affect MCM3AP-AS1 expression. The proliferation of cells investigations revealed that MCM3AP-AS1 upregulation boosted the growth of cells and diminished the detrimental impact of MEG3 upregulation on tumor growth [30,57]. Further research discovered that treating MCF7 BC cells with pterostilbene enhanced MEG3 activity. Knocking down H19, a different lncRNA, led to less cell penetration and made the cells more responsive to pterostilbene treatment. These findings imply that effec- tive optimal alteration of lncRNA expression may boost the anti-tumour properties of phytochemical compounds, potentially functioning as a therapeutic for BCs [58]. Furthermore, the research discovered that DNMT1 decreases MEG3 expression in BCs through elevating MEG3 methylation. As a result, MEG3 inhibits the proliferation of cells and development in BCs, and additional lncRNAs and DNA methylation in- fluence its levels [59].
Several variables’ effects on the rhythm of cell cycles in BC cells have been studied in various research. Cyclin D1 and its interacting associates CDK4/6, for instance, are important drivers of the development of cell cycles and have been linked to cancer growth. Inhibiting cyclin D1 or CDK4/6 promotes or lowers mobility and stem-like cell function in ER- negative and ER-positive BCs [60,61]. Another research discovered that RAD51B-depleted BC cells modified cell cycle regulation sensitivity [62]. Furthermore, the research found that Artesunate increases the arrest of the G2/M cell cycle in MCF7 BC cells via ATM stimulation [63].
Whilst these investigations do not explicitly study MEG3’s function in the modulation of major cell cycle regulators in BCs, they do shed light on the variables that influence the regulation of cell cycles in BC cells Fig. 1. The DLK1-MEG3 region is depicted in pictorial form. The maternal allele inhibited DLK1 activity by methylating this area, whereas MEG3 gene function is regulated by two DMRs, IG-DMR and MEG3-DMR.
Table 1
A condensed version of research on the involvement of MEG3 in breast cancer.
Expression Numbers of Specimens (tissues)
Signaling
Pathways Function References
Down - NF-κB and
p53 Decreases cancer proliferation, increases apoptosis
[20]
- AKT Decreases cancer
proliferation, angiogenesis, spread
[49]
90 EMT Decreases cancer
proliferation, spread
[49]
207 - - [18]
20 PI3K/Akt Decreases cancer
proliferation, spread, glycolysis, increases apoptosis
[50]
20 - Decreases cancer
spread &
metastasis
[51]
(Fig. 2).
5. Suppression of angiogenesis and metastasis 5.1. Regulation of angiogenic factors
Angiogenesis is a critical step in developing and spreading solid tu- mors, notably BCs. MEG3 has been proven to inhibit BC angiogenesis and spread (Fig. 3) [49,64]. Nevertheless, the precise mechanism of MEG3 suppresses angiogenesis and spread is uncertain. However, various processes implicated in BCs angiogenesis and spread have been found, including Hypoxia [65–67], RAB11B-AS1 (hypoxia-induced lncRNA) [68], Vascular Endothelial Growth Factor (VEGF)-dependent
and non-VEGF-dependent pathways [69], etc.
5.2. Impact on epithelial-mesenchymal transition
MEG3 has been found to regulate the EMT in BCs. MEG3 actively regulates the levels of Schlafen family member 5 (SLFN5) in BC cells via sponging miR-146b-5p, which prevents EMT and migration/invasion [70]. Another investigation found that MEG3 suppresses EMT in BCs via sponging miR-421 targeting E-cadherin [19]. However, the precise mechanism through which MEG3 regulates EMT in BCs is unknown.
Further investigations have shown numerous factors implicated in EMT in BCs, such as the integrin/ILK axis [71], INF-γ [72], and ZEB1 protein [73–75] (Fig. 3).
Fig. 2. MEG3 overexpression inhibits breast cancer growth and spread in vitro. (a) qPCR study of MEG3 expression in MDA-MB-231 and MCF-7 cells with standard or MEG3 persistently infected. (b) CCK-8 assay of standard or MEG3 MDA-MB-231 and MCF-7 proliferation of cells at the specified time. (c and d) Soft agar ex- amination demonstrates the capacity of standard or MEG3 MDA-MB-231 and MCF-7 cells to form colonies. (e and f) Transwell experiment evaluating the influence of MEG3 overexpression on the invading ability of MDA-MB-231 and MCF-7 cells (bars =100 m; *p 0.05) [63].
6. MEG3-mediated DNA damage response and genomic stability The DNA damage response (DDR) is an intricate system of molecular mechanisms in which cells have developed to forestall harmful muta- tions from being passed down to future generations. The DDR regulates the repairing of DNA with the triggering of cell-cycle checkpoints along with other responses within the cells [76]. Endogenous and environ- mental chemicals may induce the destruction of DNA, and cells have methods to identify it, announce its existence, and manage its restora- tion. The DDR is critical for preserving genomic equilibrium, which is
necessary for avoiding various human illnesses [77]. MEG3 has been implicated in DDR and genomic equilibrium. Chrysin has been demon- strated to affect the stability of the genome in BC cells by reducing DNA double-strand breakage healing. However, the impact of MEG3 on genomic equilibrium and the DDR is unclear, and more study is required to establish the precise processes engaged [78]. MEG3 also regulates the DNA damaging reaction (DDR) in ECs via the p53 network, which is a primary integrator of the DDR-induced apoptosis and cell growth. Ali et al. (2019), found that Meg3 works with PTBP3 to modulate the DDR, safeguarding the functioning of ECs. We discovered that Meg3 inhibits Fig. 3. MEG3 overexpression inhibits angiogenesis-linked activity in breast cancer. (a) qPCR study of angiogenesis-linked expression of genes in standard or MEG3 MDA-MB-231 cells. (b) ELISA study of VEGFA protein expression using either standard or MEG3 MDA-MB-231 cell culture medium. (c) qPCR study of angiogenesis- related expression of genes in standard or MEG3 MCF-7 cells. (d) ELISA study of VEGFA protein expression in standard or MEG3 MCF-7 cell culture medium. (e) VEGFA mRNA expression in 165 breast cancer specimens and 33 matching healthy breast tissues (*p 0.05). (f) In breast cancer tissues, VEGFA mRNA levels were inversely linked with MEG3 levels (Spearman’s correlation analysis, r=0.4683, p 0.0001) [70].
MEG3 has been demonstrated to behave as a competitive endogenous RNA (ceRNA) that sponges miRNAs, thereby indirectly influencing messenger RNAs (mRNAs) by functioning as miRNA sinks. According to the ceRNA speculation, lncRNAs can act as sinks for collections of miRNAs, hence influencing gene regulation at the post-transcriptional stage [80]. Furthermore, specifically single nucleotide polymorphisms (SNPs) of the H19 rs217727 and MEG3 rs7158663 loci have been linked to an increased risk of osteoarthritis. The underlying molecular pro- cesses of this connection are still being studied; however, SNPs are likely to influence the binding effectiveness of lncRNAs to miRNAs [81,83,84].
Overall, the interaction between MEG3 and miRNAs is a complicated regulatory link important in the genesis and progression of different disorders. More study is required to completely comprehend this in- teraction’s processes and find possible treatment targets.
MEG3 has been demonstrated to have interactions with a variety of miRNAs. MEG3 interacts with cyclic AMP, p53, murine double minute 2 (MDM2), and growth differentiation factor 15 (GDF15) [85]. MEG3 is additionally represented by two long intergenic RNAs, MEG3 and MEG8, those form members of the DLK1-DIO3 genomic area, with 53 miRNAs in the front thread and one (mir-1247) in the opposite thread [86]. Most of those miRNAs function differently in diverse pathologic conditions and malignancies. MEG3 has been demonstrated to operate as a ceRNA sponge for miRNAs, indirectly controlling messenger RNAs (mRNAs) by functioning as miRNA sinks [87,88]. More study is needed to completely understand the processes driving MEG3-miRNA interactions and to find possible treatment targets.
There exists proof that MEG3 and miRNAs interact in BCs. MEG3 has been found to maintain EMT in BCs cells by sponging miR-146b-5p to control SLFN51 activity [70]. Furthermore, the research discovered that the MEG3 rs7158663 G/A polymorphism related to BCs probability in the Egyptian population altered MEG3, miR-182, and miRNA-29 expression rates [6]. The DLK1-DIO3 loci, containing MEG3 and an array of over 50 miRNAs, have been demonstrated to modulate stemness in embryonic stem cells as well as cancer development, perhaps via MEG3’s suppressive function [89]. Additionally, miRNAs have been demonstrated to serve a major part in the control of EMT in BCs [90,91].
In general, the interaction between MEG3 and miRNAs is a complicated regulating link important in the genesis and advancement of BCs.
7.2. Crosstalk with protein-coding genes and other lncRNAs
BCs is a complex medical condition that includes the disruption of multiple genes and systems. MEG3 has been found to play an essential function in BCs origin. MEG3 has been discovered as a BCs tumor sup- pressor [6,29,92,93]. MEG3 has been established through investigations to be suppressed in BCs tissues relative to healthy tissues [6,29]. TP53, a key tumor suppressor molecule that inhibits tumorigenesis in breast tissue, regulates MEG3 activity [29]. MEG3 suppression has been linked to an adverse outcome in individuals with BCs [93,94].
In BCs, MEG3 has already been demonstrated to engage with various genes and networks. MEG3 can, for instance, decrease miR-21 via the PI3K/Akt cascade, which slows carcinogenesis in BCs [29]. MEG3 may
survival than those who have diminished MEG3 activity. Reduced MEG3 activity in BCs tissues was shown to be substantially linked with lymph node metastases, TNM phase, and molecular variants, and people with lower MEG3 activity had low overall survival and relapse-free prognosis [98]. A separate investigation found that MEG3 overexpression decreased BCs growth, spread, and angiogenesis via the AKT route, indicating that MEG3 may limit tumor development and angiogenesis via the AKT cascade [49,99,100]. As a result, increased MEG3 expres- sion may be used as an indicator of prognosis in individuals with BCs.
Table 2 enlists the studies on the inhibition of BCs growth and MEG3 (Table 2).
9. Challenges and future directions
MEG3 plays a multifaceted and pivotal role in the regulation of BCs, presenting a plethora of avenues for further investigation. As we delve deeper into the intricacies of MEG3’s functions, a host of challenges and promising future directions become evident. One intriguing dimension lies in context-specific regulation. MEG3 demonstrates varying impacts on distinct cell types, encompassing cancer cells, neurons, cardiac fi- broblasts, and ECs. This underscores the necessity of comprehensively grasping the mechanisms specific to each cell type [10–15]. Delving into the determinants of MEG3’s context-dependent interactions and func- tions holds the potential to reveal its diverse roles [105].
A critical aspect involves uncovering mechanistic insights. Deci- phering the intricate molecular mechanisms through which MEG3 in- fluences gene expression, cellular processes, and signaling pathways within BCs is of paramount importance [106,107]. This entails unrav- eling its intricate associations with miRNAs, transcription factors, and RNA-binding proteins. Furthermore, comprehending the epigenetic modifications that govern MEG3 expression and activity adds depth to our understanding [108,109].
Epigenetic regulation emerges as a focal point for further
Table 2
Reduction of Breast cancer by MEG3.
Findings Process References
suppresses BCs growth modulating SLFN5 expression via miR-146b-5p sponging [70]
BCs cell growth and metastasis
are inhibited AKT signaling network [49]
Piperlongumine influences MEG3, GAS5, and H19 expression in BCs cells.
- [101]
advancement, growth, spread, resistance to therapy, and prognosis of BCs.
ceRNA of miR-21 [102]
MEG3 decreases BCs cells and inhibits the aggressive growth of BCs cells
- [103]
MEG3 suppresses BCs growth,
movement, and metastasis increasing p53 gene expression on the targeted genes, notably p21, Maspin, and KAI1
[104]
exploration. Revealing the epigenetic modifications that govern MEG3 expression and their implications for BCs progression carries significant weight [110]. Understanding how DNA methylation, histone modifica- tions, and other epigenetic factors regulate MEG3 could unveil profound insights into its role in tumorigenesis [111,112]. From a clinical perspective, enhancing our comprehension of MEG3’s clinical signifi- cance is pivotal for potential diagnostic and therapeutic advancements.
Developing robust biomarkers based on MEG3 expression profiles has the potential to transform early detection, prognosis, and personalized treatment strategies for BCs patients [113].
The concept of MEG3 as a therapeutic target introduces innovative avenues for treatment. By investigating the feasibility of manipulating MEG3 expression or activity, potentially through RNA-based therapeu- tics or gene editing techniques, new prospects for tailored treatment approaches emerge. Understanding MEG3’s position within the broader network is equally crucial. Shedding light on the intricate interactions involving MEG3, other lncRNAs, miRNAs, and protein-coding genes holds the promise of a comprehensive grasp of its regulatory role [114, 115]. Employing systems biology approaches could prove instrumental in unraveling these complex networks and pinpointing strategic nodes for potential therapeutic interventions.
Moving beyond the confines of the laboratory, the trajectory involves clinical trials to assess the diagnostic and therapeutic potential of MEG3- based approaches. Successfully translating laboratory discoveries into clinical applications necessitates rigorous validation and meticulous testing in preclinical models and patient cohorts. Crucially, validating our findings is of utmost importance. Undertaking comprehensive functional studies, encompassing loss-of-function and gain-of-function experiments, CRISPR/Cas9-mediated manipulations, and animal models, will provide substantial evidence to support the observed effects of MEG3 on BCs progression, offering valuable mechanistic insights into the process.
10. Conclusion
MEG3 is a prominent lncRNA that holds a pivotal role in diverse biological processes, particularly in the realm of BC. Encoded within the imprinting DLK-MEG3 loci on human chromosomal region 14q32.3, MEG3 spans 35 kb and comprises ten exons. This imprinted gene or- chestrates an array of cellular functions through intricate interactions with miRNAs, proteins, and epigenetic alterations.
MEG3’s involvement in BC is intricate and substantial. It governs gene expression, influences the differentiation of osteogenic tissue, and contributes to various bone-related conditions. Moreover, MEG3 regu- lates apoptosis in HPMECs and HBECs induced by CSE. Additionally, MEG3 functions as a tumor suppressor in BC by modulating the expression of miR-182 and miRNA-29, and it plays roles in AMI and ECs function. Remarkably, MEG3’s interactions within the p53 network exhibit cell-specific regulatory mechanisms, leading to diverse outcomes in different cell types. MEG3’s impact on gene activity encompasses both transcriptional and post-translational modifications. DNA methylation, histone alterations, and interactions with transcription factors contribute to MEG3-mediated gene regulation. Dysregulation of MEG3 has been linked to unfavorable outcomes and drug resistance. Its in- teractions with miRNAs and protein-coding genes underscore its intri- cate involvement in BC signaling networks.
MEG3 also holds clinical significance. Elevated MEG3 expression correlates with improved survival among BC patients, suggesting its potential as a prognostic indicator. However, deciphering the complex mechanisms underlying MEG3’s functions, understanding its epigenetic control, and translating laboratory discoveries into effective clinical strategies remain challenges. Future research directions encompass unraveling context-specific interactions, delving into mechanistic in- sights, investigating epigenetic modifications, and developing MEG3- based diagnostic and therapeutic modalities. Exploring MEG3’s posi- tion within broader signaling networks and conducting rigorous clinical
trials will be pivotal. Comprehensive validation through functional studies and molecular investigations will provide valuable insights into MEG3’s intricate contributions to BC progression.
Ethics approval and consent to participant Not applicable.
Funding
This research has been funded by Scientific Research Deanship at University of Ha’il - Saudi Arabia through project number MDR-22 004.
CRediT authorship contribution statement
MSH, AAM, HA, GK and WHA wrote the draft. RUS, NEK, MKBB, RK and NA revised the manuscript. IK and SIA designed and supervised the study. RS collected the data and designed the figures and tables. All the authors read the submitted version and approved it.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
This research has been funded by Scientific Research Deanship at University of Ha’il - Saudi Arabia through project number MDR-22 004.
Consent of publication Not applicable.
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