3.1 Results of literature review
3.1.1 Literature search, characteristics of the eligible studies, and quality assessment
A total of 3,025 publications were identified through the MEDLINE/PubMed, Web of Science, and Scopus databases. After removing duplicates, authors independently assessed 928 titles and abstracts. Access to around 60 full-text papers was unavailable due to journal copyrights and restrictions. Irrelevant papers were excluded based on the exclusion criteria, and finally, 288 studies met the eligibility criteria. The selection process is illustrated in Fig. 2.
All studies were published in English between 2007 and 2024 and investigated various types and stages of metastatic breast cancer. All studies examined the effects of ncRNAs on BC metastasis and invasion. Among them:
- 347 studies used only cell lines to investigate their hypotheses
- Three studies utilized just the patient's blood/serum sample
- 158 studies included in vivo experiments in animal models
- 224 studies also included human tissue specimen
These studies identified:
- 79 miRNAs and their target genes.
- 117 studies describing lncRNAs and their miRNAs/mRNAs targets
- 43 studies illustrating circRNAs and their targeted miRNAs/mRNAs.
- 50 studies introducing ncRNAs without specifying their targets.
The details of the included studies are provided in the Supplementary Table. 1.
3.2 Results of bioinformatics investigations
3.2.1 Putative targets of miRNAs, lncRNAs, and circRNAs
Bioinformatics target predictions were conducted using specific approaches for 50 of the studies that did not specify a target for the ncRNA. Targeted mRNAs of 10 miRNAs were identified by accessing the three validated databases MiRTarBase, Targets can, and miRDB via the multiMiR (R-package). To identify the miRNAs associated with 37 lncRNAs, we utilized the Encase database. In addition, the Circular RNA Interactome database was used to extract the target miRNAs of the acquired three circRNAs. Finally, a multiMiR R-package was utilized to identify mRNA targets for miRNAs.
3.2.2 Construction of ceRNA-network and PPInetwork; key hubs and module identification
Using the Cytoscape software, we established an interaction network to identify the interrelationships between 2752 mRNAs extracted from the constructed ceRNA network. Afterward, the disconnected nodes were removed, and then the network included 2264 nodes and 6705 edges through the CytoHubba and MCODE plugins. After selecting the 50 most dysregulated factors among the three most important network characteristics (betweenness, closeness, and degree) using the cytoHubba plug-in for network visualization, 11 shared most significant dysregulated factors were identified by Venn diagram (https://bioinfogp.cnb.csic.es/tools/venny/) (Fig. 3A). They were hsa-miR-1, has-miR-9, has-miR-27 b, has-miR-20 b, has-miR-21, has-miR-335, has-miR-139, ITGB1, MALAT1, CXCR4, and TGFB1 (Fig. 4). Subsequently, the MCODE plugin was utilized to obtain the significant modules from the PPI-network. The significant module (module 1) contained 32 nodes and 507 edges (Fig. 3B).
3.2.3 Pathways retrieved by functional enrichment analysis
The Enrichr database was used to undertake functional enrichment analysis of the mRNAs in module 1 attained from the PPI-network to better understand the underlying mechanisms of BCM.
Proteoglycans in cancer, microRNAs in cancer, pathways in cancer, and signaling pathways governing the pluripotency of stem cells were among the biological pathways that were the focus of the KEGG pathway (Fig. 5A) study the pathways indicated above.
Biological process (BP), molecular function (MF), and cellular component (CC) were identified by GO enrichment analysis. Positive and negative control of cell differentiation, control of pri-miRNA transcription by RNA polymerase II, control of the epithelial to mesenchymal transition, proliferation, angiogenesis, and the apoptotic process were the key topics of the BP enrichment process for GO analysis (Fig. 5B). Meanwhile, CC enrichment mainly consisted of cyclin-dependent protein kinase holoenzyme complex and serine/threonine protein kinase complex (Fig. 5C). MF enrichment mainly featured transcription cis-regulatory region binding and ubiquitin protein ligase binding (Fig. 5D).
3.2.4 Survival and expression analysis
Using the Kaplan-Meier plotter, we investigated the relationship between the expression of 11 hub RNAs extracted from the ceRNA-network and the prognosis of BC patients. For this purpose, the BC samples were grouped based on the median expression of each gene, and these two groups were evaluated with the log-rank test. Our results showed that among 11 hubs, three miRNAs, hsa-miR-1 (p-value= 0.00012), hsa-miR-9 (p-value= 0.0016), and hsa-miR-27 b (p-value= 0.027), in addition to one lncRNA, MALAT1 (p-value= 0.039) had a significant relationship with the overall survival of BC patients. The remaining hubs did not show significant connections with poor prognosis (p-value≥0.05) (Fig. 6).
3.3 Synthesis of results
3.3.1 Metastasis procedure in BC:
Breast cancer metastasis (BCM) is the main cause of death for most patients and a significant therapeutic issue (53,54). It is a multi-step process by which tumor cells move from primary tumors to secondary sites, spreading to distant body organs, particularly the lung, liver, bone, and brain (6). Invasion, intravasation, circulation, extravasation, and metastatic outgrowth (or colonization) are some of the many steps in this highly complicated process (55). During invasion, the process by which disseminated tumor cells (DTCs) split off from their source, migrate to other places and transform localized cancer into a systemic disease is known as the metastatic cascade (4,56) (Fig. 7).
EMT is a major driver of cancer metastasis, with the ability to enhance stem cell-like traits in tumor cells which acquire self-renewal abilities (57,58). By mimicking an embryonic transition, these cells detach from the primary tumor, enter the bloodstream, and spread, fueling disease progression (59,60). During this process, they gain the ability to move, invade, and separate from epithelial cell sheets (61,62). Breast cancer stem cells (BCSCs) contribute to organ-specific metastasis by interacting with distant organ environments and promoting pre-metastatic niches (63). They also provide high motility and resistance to apoptosis (4). Key signaling pathways, including Wnt, Notch, PI3K/Akt, and TGF-β, play crucial roles in EMT and cancer stemness, driving metastasis (64,65). Non-coding RNAs, particularly microRNAs, contribute to regulatory networks by targeting key regulators in metastatic cascade (66–68). Gaining insight into this crosstalk amongst networks may help identify which nodes of interaction to focus on to address several of the harmful phases of the metastatic pathways at once (69). Along with these, it has been discovered that the TWIST1, SLUG, SNAIL, ZEB1, ZEB2, and FOX families are transcriptional inhibitors of E-cadherin BCSCs also showed strong expression of these genes as EMT markers and a markedly enhanced potential for self-renewal and tumor initiation (70–72). By controlling different gene expression in different combinations, these EMT transcription factors (EMT-TFs) and CSC transcription factors (CSC-TFs) are closely linked to the development, spread, invasion, and metastasis of cancer as well as chemo-resistance (73–75).
Detecting the disease early before metastasis can improve survival and allow the adoption of the best strategy for disease management, targeted therapy, and personalized medicine. Despite the numerous investigations in this context, understanding the spread of BC is still unclear, with major molecular regulators crucial for its development. Therefore, in light of the results mentioned above, we have attempted to conduct a more thorough investigation into BCM by evaluating prior research and building a ceRNA-network to help identify the underlying mechanism and pave the way for future investigations.
3.3.2 The role of miRNAs in Breast Cancer Metastasis:
MicroRNAs (miRNAs) are small, ~21–25 nucleotide (nt), regulatory RNA molecules that have been demonstrated to post-transcriptionally modify gene expression in a variety of biological pathways through complex regulatory networks and highly precise interactions (76). By binding to one or more sites within the 3' untranslated region (UTR) of several target mRNAs, they control genes by degrading or repressing mRNAs' translation (76). Recent studies have elucidated miRNAs' critical role in cancer cell metastatic spread (77). These miRNAs are referred to as ‘’metastamiRs” (78). Based on their target genes, certain miRNAs can have tumor-suppressive qualities (tsmiR) because the majority of miRNAs function by inhibiting their target genes (79). If its target is an oncogene, it can promote carcinogenesis (oncomiR) (80). According to several recent research, miRNAs can be dysregulated in tumor tissues and are essential for the spread of BCM (77).
In this manner, many studies demonstrated that the overexpression of miR-10b by transcription factor Twist can act as oncomiR and is directly associated with BCM by regulating HOXD10 as its target gene (81–83). Several studies revealed the upregulation of miR-21 as another oncomiR that may increase BCM by controlling TIMP3 translation, especially in HER-2+ BC (84–87). Besides, BCM is caused by uncontrolled Wnt/β-catenin signaling that results from inactivating GSK3β and miR-29 upregulates the N-Myc oncogene (88). Additionally, in ERα- BC and TNBC, miR-29a overexpression is associated with distant metastasis and poor survival through targeting PTEN and inducing EMT and metastasis via AKT signaling (89). Along with oncogenic ras signaling, miR-29a can also inhibit tristetraprolin (TTP), a protein that breaks down messenger RNAs with AU-rich 3′-untranslated regions, resulting in EMT, metastasis, and BCM (90). It has also been reported that overexpression of miR-9 contributes to BCM development (91–93). It increases BC cell motility and promotes invasion, metastasis, and angiogenesis by regulating FOXO1 and E-cadherin (94).
Regarding the suppressive effects of miRNAs on BCM, research has shown that increases in miR-126 expression levels can function as a tsmiR to prevent BC invasion and metastasis by directly inhibiting a disintegrin and metalloprotease 9 (ADAM9) (95) or by targeting and modifying the gene expressions of VEGF/PI3K/AKT and MAPK signaling (96). Additionally, as a tumor suppressor, miR-145 directly targets mucin1 (MUC1) and Fascin-1 (FSCN1) (97), and through Fascin-1, c-Myc, SMAD2/3, IGF-1R indirectly down-regulates Wnt signaling pathway and suppress BC cell invasion and metastasis (98). Mohammadi-Yeganeh et al. introduced miR-340 as a tsmiR and reported that it targets Wnt signaling and that its expression significantly decreased in BC metastatic cells. They also asserted that miR-340 can bind to the 3′-UTRs of CTNNB1, c-MYC, and ROCK1 oncogenes, inhibiting its oncogenic effects in BC cells (99). In the other study, the c-Met oncogene was considered a direct target of miR-340 to indirectly downregulate MMP-2 and MMP-9 expression and inhibit BC invasion and metastasis (100). Besides, upregulation of miR-512-3p can directly target the 3’UTR of Livin and decrease its expression, inhibiting BC invasiveness and metastasis (101). Similarly, miR‐515‐5p can inhibit BC cell migration and metastasis by binding to 3′ UTR of MARK4 and inhibiting its expression (102).
There is conflicting evidence about the involvement of certain miRNAs in the development of BCM. As a typical example, members of the miR-200 family have been shown to play a significant part in BCM to regulate the invasion and migration of BC cells. However, some studies uncover their promoting activities, others expose their inhibitory impacts (103). In this notion, it has been revealed that in TNBC cells, IMP2 and IMP3 increase EMT and metastasis by directly targeting miR-200a and repressing its transcription, which downregulates progesterone receptor (PR) via IMP2/3-miR-200a-PR negative feedback loop (104). According to Roy et al., PELP1 controls the expression and activities of the tumor metastasis suppressors miR-200a and miR-14, hence regulating BC tumor metastasis (105). Comparably, Li et al. discovered that the expression of miR-200b/200c/429 functional groups, but not miR-141/200a, in a xenograft orthotopic model of BC limits tumor cell invasion and metastasis (106). Likewise, miR-200a directly interacts with 3′UTR of the EPHA2 oncogene and inhibits BC cell migration dually; regulating the well-characterized E-cadherin pathway regulates the EPHA2 pathway (107). Furthermore, miR-200b was shown to target moesin directly and restore it in cells expressing miR-200b to reduce metastatic features (106). In TNBC cells, miR-200b targets PKCα and reduces Rac1 activity to suppress invasion and tumor metastasis (108). Zhang G et al. discovered in a study that when FOXP3-KAT2B regulates miR-200c/141, these miRNAs' plasma levels rise in metastasis compared to individuals with localized BC (109). It is also demonstrated that compared to matching primary tumors, distant metastasis exhibits increased levels of miR-200 and miR-9 (93). In addition, BC cell line overexpression of miR-200c in mice targets Zeb2 and inhibits its expression, leading to MET and macroscopic metastasis (110).
Another significant and contradictory miRNA that is involved in BCM is miR-206. Accordingly, Zhou Y et al. found that overexpression of miR-206 in BC cell lines and tissues enhances invasion and migration through binding to the 3′-UTR of full-length neurokinin-1 mRNA and controlling its protein production (111). Further, it was discovered that overexpression of miR-206 in the transfected BC cell lines diminished Cdc42 in addition to MMP-2 and MMP-9, thereby suppressing invasion and migration (112). Nevertheless, Adorno-Cruz et al. identified that BC stemness and metastasis are linked to low levels of miR-206, which targets and upregulates ITGA2 as well as its downstream genes ACLY and CCND1 (113). Moreover, a study identified that when the expression of the miR-206 was significantly lower than that in the primary breast tumor, the expression of the Cx43 protein was significantly higher in the liver, and pulmonary metastasis, migration, and invasion capacities were improved (114). MiR-1, considered a crucial regulator of tumor metastasis, has been mentioned that it functioned as a time by targeting K-RAS oncogene and lncRNA MALAT1 inhibited BC cell motility and invasion (115). In a study, Peng et al. found that overexpressed miR-1 in BC cells, which can bind to 3′-UTR of the Bcl‑2, can prevent invasion, migration, and metastasis Through the downregulation of miR-1, MALAT1 has been shown to act as a ceRNA of cdc42' 3′-UTR or via MALAT1miR-1/slug axis, causing BC cells to migrate and invade(116,117). However, Minemura et al. demonstrated that miR-1 overexpression is associated with poor prognosis and distant metastasis of BC patients (118). Table. 2 thoroughly represent miRNAs regulate BCM.
Table. 2. The list of miRNAs involved in BCM regulation.
|
MiRNA
|
Regulation
|
Target
|
Detection Method(s)
|
Authors
|
Year
|
Title
|
|
miR-10b
|
Up
|
NA
|
qRT-PCR
|
Alan Halim et al
|
2024
|
(83)
|
|
miR-29a
|
Up
|
PTEN
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Jinhui Lü et al
|
2023
|
(89)
|
|
miR-5694
|
Up
|
AF9/Snail
|
qRT‐PCR, Dual‐luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Xin Tian et al
|
2021
|
(119)
|
|
miR-26 and miR-101
|
Down
|
COX-2
|
qRT‐PCR, Dual‐luciferase reporter assay, Trans-endothelial migration assay
|
Rania Harati et al
|
2021
|
(120)
|
|
miR-301
|
Up
|
CPEB1/SIRT1/SOX2
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assay
|
Yanjing Jia et al
|
2021
|
(121)
|
|
miR-206
|
Down
|
ITGA2/CD49b
|
qRT-PCR, Luciferase reporter assay, Scratch wound assays of cell migration and invasion
|
Valery Adorno-Cruz et al
|
2021
|
(113)
|
|
miR-934
|
Up
|
PTEN
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Yexia Lu et al
|
2021
|
(122)
|
|
miR-181b-3p
|
-
|
FTO/miR-181b-3p/ARL5B
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell assay
|
Yuanyuan Xu et al
|
2020
|
(123)
|
|
miR-512-3p
|
Down
|
Livin
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
W. J. Duan et al
|
2020
|
(101)
|
|
miR-382-5p
|
Up
|
MXD1
|
qRT-PCR, Matrigel Invasion Assay
|
Xiliang Zhang et al
|
2020
|
(124)
|
|
miR-6744-5p
|
Down
|
NAT1
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Sharan Malagobadan et al
|
2020
|
(125)
|
|
miR-1
|
Down
|
Bcl‑2
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assay
|
Jing Peng et al
|
2020
|
(126)
|
|
miR-106a
|
UP
|
DAX-1
|
qRT-PCR, Transwell migration and invasion assay
|
C. Liu et al
|
2019
|
(127)
|
|
miR-3184-5p, miR-181c-3p
|
miR-3184-5p Up
miR-181c-3p Down
|
FOXP4 for miR‐3184‐5p, PPARα for miR‐181c‐3p
|
qRT‐PCR, Matrigel invasion assay, Scratch assay
|
Dheeran Rajarajan et al
|
2019
|
(128)
|
|
miR-155
|
UP
|
MAPK7
|
qRT-PCR, Wound healing assay, Transwell invasion assay
|
Jian-Hua Liu et al
|
2019
|
(129)
|
|
miR-331, miR-195
|
mir-331 Up
mir-195 Down
|
NA
|
qRT-PCR
|
Peter McAnena et al
|
2019
|
(130)
|
|
|
|
|
|
|
|
|
|
miR-206
|
UP
|
NK1R-FL
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Yu Zhou et al
|
2019
|
(111)
|
|
miR-454-3p
|
Up
|
RPRD1A, AXIN2, DKK3, SFRP1
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Liangliang Ren et al
|
2019
|
(131)
|
|
miR‑133b
|
Down
|
TGFβR1
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assay
|
Shengjie Wang et al
|
2019
|
(132)
|
|
miR-638
|
Down
|
CREB1/Lin28/miR-638/VASP
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Peng-Chao Hu et al
|
2019
|
(133)
|
|
miR-218
|
Up
|
Col1a1/INHBB/YY1
|
qRT-PCR
|
Xuxiang Liu et al
|
2018
|
(134)
|
|
miR-130a
|
Down
|
FOSL1/ZO-1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Xiaowei Chen et al
|
2018
|
(135)
|
|
miR-200a
|
Down
|
IMP2/3-miR-200a-PR
|
qRT‐PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Hye-Youn Kim et al
|
2018
|
(104)
|
|
miR-203
|
Up
|
bach1/MMP-9/CXCR4 receptor
|
qRT-PCR
|
Reza Mohammadzadeh et al
|
2017
|
(136)
|
|
miR-381
|
Down
|
CXCR4
|
qRT-PCR, Luciferase reporter assay, Cell migration and invasion assay
|
Yubao Xue et al
|
2017
|
(137)
|
|
miR-130b-3p
|
Down
|
DLL1
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assay
|
Yifang Shui et al
|
2017
|
(138)
|
|
miR-19b
|
Up
|
PTENP1, PTEN
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
R-K Li et al
|
2017
|
(139)
|
|
miR-125b
|
-
|
StarD13/miR-125b/TP53INP1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Lufeng Zheng et al
|
2017
|
(140)
|
|
miR-200c
|
-
|
FOXP3/KAT2B
|
TaqMan miR assay, Nest-qPCR
|
Guangxin Zhang et al
|
2017
|
(109)
|
|
miR‑206
|
Down
|
Connexin 43
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Zi-Jing Lin et al
|
2016
|
(114)
|
|
miR-340
|
Down
|
CTNNB1, c-MYC, ROCK1
|
qRT‐PCR, Dual‐luciferase reporter assay, Transwell migration and invasion assay
|
Samira Mohammadi-Yeganeh et al
|
2016
|
(99)
|
|
miR-152
|
Down
|
DNMT1/CDH1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay
|
Dipta Sengupta et al
|
2016
|
(141)
|
|
miR-497
|
Down
|
ERRα
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Li Han et al
|
2016
|
(142)
|
|
miR-448
|
Down
|
MALAT1/KDM5B
|
qRT-PCR, Transwell invasion assay
|
Oluwaseun Adebayo Bamodu et al
|
2016
|
(143)
|
|
miR-515-5p
|
Down
|
MARK4
|
qRT-PCR, Luciferase reporter assay, Cell tracking assay, Boyden chamber assay
|
Olivier E Pardo et al
|
2016
|
(102)
|
|
miR-548j
|
Up
|
Tensin1
|
qRT-PCR, Transwell invasion assay
|
Yun Zhan et al
|
2016
|
(144)
|
|
miR-490-3p
|
Down
|
TNKS2
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Zhongming Jia et al
|
2016
|
(145)
|
|
miR-126
|
Down
|
VEGF/PI3K/AKT
|
qRT-PCR, Wound healing assay, Transwell invasion assay
|
D Turgut Cosan et al
|
2016
|
(96)
|
|
miR-146a
|
Down
|
CXCR4, TRAF6, EGFR
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Tianjing Zheng et al
|
2015
|
(146)
|
|
miR-126
|
Down
|
ADAM9
|
qRT-PCR, Matrigel invasion assay
|
Cheng-Zheng Wang et al
|
2015
|
(95)
|
|
miR-1
|
Down
|
K-RAS, MALAT1
|
qRT-PCR, Dual-luciferase reporter assay, Transwell invasion assay
|
Ruilei Liu et al
|
2015
|
(115)
|
|
miR-1
|
Up
|
NA
|
MicroRNA PCR array, IHC
|
Hiroyuki Minemura et al
|
2015
|
(118)
|
|
miR-20b
|
UP
|
NA
|
qRT-PCR, Transwell invasion assay
|
Aamir Ahmad et al
|
2015
|
(147)
|
|
miR-21
|
Up
|
NA
|
qRT-PCR
|
Eman A Toraih et al
|
2015
|
(86)
|
|
miR-9
|
Down
|
NOTCH1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Samira Mohammadi-Yeganeh et al
|
2015
|
(148)
|
|
miR-509
|
Down
|
RhoC, TNF-α
|
qRT‐PCR, Dual‐luciferase reporter assay, Wound healing assay, Transmigration assays
|
Fei Xing et al
|
2015
|
(149)
|
|
miR-191
|
Up
|
TGFβ2, HuR
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell migration and invasion assays
|
Neha Nagpal et al
|
2015
|
(150)
|
|
miR-200a
|
Down
|
EPHA2
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Efrosini Tsouko et al
|
2015
|
(107)
|
|
miR-9
|
Up
|
FOXO1, E-cadherin
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration assay, Adhesion assay
|
Jue Yang et al
|
2014
|
(94)
|
|
miR-10b
|
Up
|
HOXD10
|
qRT-PCR
|
Paola Parrella et al
|
2014
|
(81)
|
|
miR-106b
|
Down
|
MMP2
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Xiaojian Ni et al
|
2014
|
(151)
|
|
miR-183, miR-494, miR-21
|
-
|
NA
|
qRT-PCR
|
Augusto LF Marino et al
|
2014
|
(152)
|
|
miR-29
|
Up
|
NMI
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Jack W Rostas III et al
|
2014
|
(88)
|
|
miR-720
|
Down
|
TWIST1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Lin-Zi Li et al
|
2014
|
(153)
|
|
miR-429
|
Down
|
ZEB1, CRKL
|
qRT-PCR, Transwell invasion assay
|
Zhi-bin Ye et al
|
2014
|
(154)
|
|
miR-200b
|
Down
|
PKCα
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Brock Humphries et al
|
2014
|
(108)
|
|
miR-127
|
Down
|
BCL6
|
qRT-PCR, Wound healing assay, Transwell invasion assay
|
Xiujuan Zhao et al
|
2013
|
(155)
|
|
miR-21
|
Up
|
TIMP-3
|
qRT-PCR
|
Jianyi Li et al
|
2013
|
(85)
|
|
miR-200a, miR-141
|
Down
|
ZEB1, ZEB2
|
qRT-PCR, Luciferase reporter assay, Cell Migration and Invasion Assays
|
Sudipa Saha Roy et al
|
2013
|
(105)
|
|
miR-200b
|
Down
|
moesin
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
X Li et al
|
2013
|
(106)
|
|
miR-135a
|
UP
|
HOXA10
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Yating Chen et al
|
2012
|
(156)
|
|
miR-151-5p, miR-9
|
miR-151-5p Down
|
NA
|
qRT-PCR
|
Jonathan Krell et al
|
2012
|
(91)
|
|
miR-21
|
Up
|
NA
|
qRT-PCR
|
Shahram Savad et al
|
2012
|
(84)
|
|
miR-224
|
UP
|
RKIP
|
qRT-PCR, Wound healing assay, Transwell invasion assay, 3D spheroid invasion assay
|
Lin Huang et al
|
2012
|
(157)
|
|
miR-200, miR-9
|
UP
|
NA
|
qRT-PCR, ISH
|
Karina H. Gravgaard et al
|
2012
|
(93)
|
|
miR-340
|
Down
|
c-Met
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Zheng-sheng Wu et al
|
2011
|
(100)
|
|
miR-145
|
Down
|
Fascin-1, c-myc, SMAD2/3, IGF-1R
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Seok-Jun Kim et al
|
2011
|
(98)
|
|
miR-1258
|
Down
|
HPSE
|
qRT-PCR, Luciferase reporter assay, Cell invasion assays
|
Lixin Zhang et al
|
2011
|
(158)
|
|
miR-183
|
-
|
VIL2
|
qRT-PCR, Transwell migration assay
|
Aoife J Lowery et al
|
2010
|
(159)
|
|
miR-206
|
-
|
Cdc42, MMP-2, MMP-9
|
qRT-PCR, Transwell migration and invasion assay
|
Hao Liu et al
|
2010
|
(112)
|
|
miR-103/107
|
Up
|
Dicer/mir-200
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Graziano Martello et al
|
2010
|
(160)
|
|
miR-17-5p
|
UP
|
HBP1/β-catenin
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Hongling Li et al
|
2010
|
(161)
|
|
miR-196s
|
-
|
HOXC8
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Yong Li et al
|
2010
|
(162)
|
|
miR-17/20
|
Down
|
IL-8
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Zuoren Yu et al
|
2010
|
(163)
|
|
miR-145
|
Down
|
MUC1
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Mohit Sachdeva et al
|
2010
|
(97)
|
|
mir-520h
|
up
|
PP2A/C
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Jen-Liang Su et al
|
2010
|
(164)
|
|
miR-21
|
Up
|
TIMP3
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Bao Song et al
|
2010
|
(87)
|
|
miR-205
|
Down
|
ErbB3, VEGF-A
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Hailong Wu et al
|
2009
|
(165)
|
|
miR-661
|
Down
|
c,EBPα/ miR-661/MTA1
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Sirigiri Divijendra Natha Reddy et al
|
2009
|
(166)
|
|
miR-17-92
|
UP
|
NA
|
qRT-PCR, Wound healing assay, Transwell migration assay
|
Sijin Liu et al
|
2009
|
(167)
|
|
miR-27b
|
UP
|
ST14
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Yanfang Wang et al
|
2009
|
(168)
|
|
miR-29a
|
UP
|
TTP
|
qRT-PCR
|
Christoph A Gebeshuber et al
|
2009
|
(90)
|
|
miR-193b
|
Down
|
uPA
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
X-F Li et al
|
2009
|
(169)
|
|
miR-373 and miR-520c
|
UP
|
CD44
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Qihong Huang et al
|
2008
|
(170)
|
|
miR-7
|
Down
|
Pak1
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Sirigiri Divijendra Natha Reddy et al
|
2008
|
(171)
|
|
miR-155
|
UP
|
RhoA
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
William Kong et al
|
2008
|
(172)
|
|
miR-335
|
Down
|
SOX4, PTPRN2, TNC, MERTK
|
qRT‐PCR, Dual‐luciferase reporter assay, Transwell migration and invasion assay
|
Sohail F Tavazoie et al
|
2008
|
(173)
|
|
miR-10b
|
UP
|
HOXD10, RHOC
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Li Ma et al
|
2007
|
(82)
|
3.3.3 The role of lncRNAs in Breast Cancer Metastasis:
Long non-coding RNAs are a category of ncRNAs longer than 200 nucleotides (174). Chromosome rearrangement, histone modification, transcription, stabilizing mRNA, and altering alternative splicing sequences are just a few of the physiological processes regulated by lncRNAs. Consequently, they are accountable for a large number of diseases, including cancer (175). As competitive endogenous RNAs and sponging miRNAs, lncRNAs have been shown to influence multiple signaling pathways and regulate the synthesis of proteins associated with invasion, migration, EMT and metastasis (23,175,176). Accordingly, the spread of the malignant process of BC cell invasion and metastasis might result from modifications to the several signaling pathways that govern lncRNAs' regulation (176,177).
As an illustration, the TGF-β signaling pathway is a key regulator of the EMT process by affecting the expression of EMT-associated factors, such as ZEB, E-cadherin, Vimentin, and SNAIL (178–180). In line with this, Li et al. indicated that following induction of lncATB by TGF-β treatment, EMT markers such as ZEB1, Twist1, N-Cadherin, and Vimentin are upregulated while E-Cadherin is downregulated. They discovered that lncATB, which acts as a sponge for the miR-200 family and restores Twist1 expression, can promote cell invasion and migration in vitro and in vivo and is linked to distant metastasis (181). Furthermore, TGF-β-induced migration, invasion, EMT, and metastasis were prevented by suppressing lncRNA-HIT (HOXA transcript produced by TGFβ), which has E-cadherin as one of its major targets. Nevertheless, metastatic cells exhibited a significant increase in lncRNA-HIT expression (182). In a study conducted by Li GY et al., UCA1 functions as a competitive endogenous RNA (ceRNA) in the cytoplasm, whereas AC026904.1 functions as an enhancer RNA in the nucleus. LncRNAs AC026904.1 and UCA1 are also overexpressed in both canonical and non-canonical TGF-β pathways. They target and activate SLUG in BC cells to promote EMT and metastasis (183). There are controversial studies around the role of CASC2 in BCM. Two investigations illustrated the upregulation of CASC2 contributes to BCM progression by targeting TGF-β signaling-associated genes such as TGFB1, SMAD2, and α-SMA (184). On the other hand, two different studies reported that CASC2 has an inhibitory effect on BCM through the miR-96-5p/SYVN1 axis (185), and inactivation of the TGF-β signaling pathway is involved in its function (186). ARHGAP5-AS1 inhibits BC invasion and metastasis by inhibiting SMAD7 and impeding the TGF-β signaling pathway (187).
The Wnt signaling pathway is known to be essential for regulating the development of embryonic organs and the advancement of cancers, especially since it plays a crucial role during the BCM process (188). There is mounting evidence that lncRNAs control Wnt signaling, which either promotes or inhibits the growth of BCM (189). In light of this, lncRNAs DGCR5, EZR‑AS1, LINC01287, RUSC1‑AS‑N, and HOTTIP have been found to promote BC invasion, EMT, and metastasis through their modulation of the Wnt/β-catenin signaling pathway (190–194). Multiple studies demonstrated that H19 could promote BC invasion and metastasis (195). In a ceRNA-network, H19 can competitively bind miR-200b/c and let-7 to regulate Lin28, Git2, and Cyth3 and accelerate BCM (196,197), or it can sponges miR-340-3p and enhance BCM and EMT by regulating YWHAZ and potentiating the Wnt/β-catenin signaling (198). Tan et al. discovered that lncRNA LINC00511 encodes the small peptide LINC00511-133aa and by controlling the expression levels of proteins related to the Wnt/β-catenin pathway, such as Bax, c-myc, and CyclinD1, and facilitating β-catenin protein entry into the nucleus, increased the invasiveness and stemness of BC cells (199). Overexpression of LncCCAT1 influences BCSC stemness, migration, and invasion capabilities (200). It potentially enhances T-cell factor 4 and triggers Wnt signaling through interactions with miR-204/211, miR-148a/152, and ANXA2 (200).
In terms of epigenetic regulation, by engaging DNA methyl transferase and triggering the Wnt signaling pathway, LINC00518 increases CDX2 methylation and facilitates the metastasis and development of BC (201). Additionally, LINC00922 controls BC invasion, migration, and EMT by promoting NKD2 methylation and activating the Wnt signaling pathway (202). In contrast, the Wnt/β-catenin signaling pathway in BC is inhibited by LINC01089, which also predicts the clinical prognosis. Zhang et al. further showed that by directly targeting SFRP1 and DKK2/3, miR-586 induced Wnt/β-catenin activation and acted as an oncogene to promote BC progression and invasion (203). LINC01189 functioned as a tumor suppressor and inhibited BC progression by inhibiting EMT-like phenotype by sponging miR-586 in the LINC01189/miR-586/ZEB1 feedback loop (204). Fig. 8 depicts the interactions of lncRNAs in the process of BCM via a crucial signaling pathway.
Moreover, NEAT1, MALAT1, HOTAIR, and linc-ROR are well-known lncRNAs that promote BCM via ceRNA-networks, sponging miRNAs and regulating essential genes (205,206,215–217,207–214). There are three studies mentioned the role of AFAP1-AS1 in BCM (218–220). According to Chen C et al., TNBC primary cells with elevated AFAP1-AS1 levels expressed more downstream genes of the PLK1 pathway, including CDC25C, CDK1, BUB1, and TTK. More significantly, in a mouse metastatic model, AFAP1-AS1 boosted lung metastases (219). Zhang X et al. discovered in a different study that AFAP1-AS1 stimulates TNBC cell invasion via regulating MTH1 expression by targeting miR-145 (220). Table. 3 thoroughly illustrates the studies that investigated the function of lncRNAs in BCM.
Table. 3. List of the research that examined the regulation of lncRNAs in BCM.
|
LncRNA
|
Regulation
|
Target
|
Detection Method(s)
|
Authors
|
Year
|
Title
|
|
LINC01569
|
Down
|
miR-300/FILIP1L
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Xinyu Jiang et al
|
2024
|
(221)
|
|
LYPLAL1-DT
|
Down
|
hnRNPK/β-Catenin
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell assay
|
Yuhui Tang et al
|
2023
|
(222)
|
|
T376626
|
Up
|
LAMC2
|
qRT-PCR, RNA pulldown assay, Wound healing assay, Transwell migration and invasion assay
|
Yongyin He et al
|
2023
|
(223)
|
|
TMEM105
|
Up
|
miR-1208/LDHA
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Jinzhu Han et al
|
2023
|
(224)
|
|
MIR17HG
|
Down
|
miR-454-3p/FAM135A
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Jingjing Xu et al
|
2023
|
(225)
|
|
LncRNA‑BC069792
|
Down
|
miR-658, miR-4739/KCNQ4
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Yunxiang Zhang et al
|
2023
|
(226)
|
|
LINC00511
|
Up
|
NA
|
qRT-PCR, Wound healing assay, Transwell invasion assay
|
Zhongqiu Tan et al
|
2023
|
(199)
|
|
OBSCN-AS1
|
Down
|
OBSCN
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell migration assay, 3D collagen invasion assay
|
Talia Guardia et al
|
2023
|
(227)
|
|
LINC00478
|
Down
|
PHB2/c-Myc
|
qRT-PCR, RIP, Wound healing assay, Transwell migration and invasion assay
|
Rong Guo et al
|
2023
|
(228)
|
|
AFAP1-AS1
|
Up
|
PLK1, CDC25C, CDK1, BUB1, TTK
|
qRT-PCR, Transwell migration and invasion assay
|
Shuizhong Cen et al
|
2023
|
(218)
|
|
LINC01559
|
Up
|
miR-370-3p/miR-485-5p/miR-940
|
qRT-PCR, Luciferase reporter assay, Wound healing and Transwell assays
|
Xue Yang et al
|
2022
|
(229)
|
|
TCONS_00068220
|
Up
|
CDH1
|
qRT-PCR, Transwell migration and invasion assay
|
Xiao Liu et al
|
2021
|
(230)
|
|
ENST00000508435
|
Up
|
FXR1
|
qRT-PCR, RIP, Wound healing assay, Transwell migration assay
|
Luying Li et al
|
2021
|
(231)
|
|
LINC00483
|
Up
|
IGF2BP1
|
qRT-PCR, RIP
|
Y.-S. QIAO et al.,
|
2021
|
(232)
|
|
SPINT1-AS1
|
Up
|
let-7a/b/i-5p
|
qRT-PCR, Wound-healing assay, Transwell migration and invasion assay
|
Tongzhou Zhou et al
|
2021
|
(233)
|
|
|
|
|
|
|
|
|
|
LINC00472
|
Down
|
MCM6
|
qRT-PCR, RIP, Wound healing assay, Transwell invasion assay
|
Guoli Shao et al
|
2021
|
(234)
|
|
DGUOK-AS1
|
Up
|
miR-204-5p/IL-11
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Yiran Liang et al
|
2021
|
(235)
|
|
MALAT1
|
Up
|
miR‑26a/26b/ST8SIA4
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Cell migration and invasion assays
|
Nan Wang et al
|
2021
|
(213)
|
|
RACGAP1P
|
UP
|
miR-345-5p/RACGAP1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Danmei Zhou et al
|
2021
|
(236)
|
|
SChLAP1
|
Up
|
miR‑524‑5p/HMGA2
|
qRT-PCR, Luciferase reporter assay
|
Xiangdong Bai et al
|
2021
|
(237)
|
|
LINC01189
|
Down
|
miR-586/ZEB1
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Matrigel Invasion Assay
|
Di Zhang et al
|
2021
|
(203)
|
|
DSCAM-AS1
|
Up
|
NA
|
qRT-PCR
|
Mahsa Tarighi et al
|
2021
|
(238)
|
|
LINC00922
|
Up
|
NKD2
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
Yan Wang et al
|
2021
|
(202)
|
|
LINC00926
|
Down
|
PGK1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Zhong Chu et al
|
2021
|
(239)
|
|
NEAT1
|
Up
|
PGK1/PGAM1/ENO1 Complexes
|
qRT-PCR, Transwell invasion assay
|
Mi Kyung Park et al
|
2021
|
(209)
|
|
ARHGAP5-AS1
|
Down
|
SMAD7
|
qRT-PCR, Dual-luciferase reporter assay,Transwell assay, F-actin staining
|
Chen‑Long Wang et al
|
2021
|
(187)
|
|
SNHG1
|
UP
|
STAT6
|
qRT-PCR, Transwell invasion assay
|
Shoukai Zong et al
|
2021
|
(240)
|
|
AC073352.1
|
Up
|
YBX1
|
qRT-PCR, Wound-healing assay, Transwell migration and invasion assay
|
Xue Kong et al
|
2021
|
(241)
|
|
ZEB2NAT
|
-
|
ZEB2
|
Transwell invasion assay
|
Canan Eroğlu Güneş et al
|
2021
|
(242)
|
|
LncRNA-CCRR
|
Up
|
CX43
|
qRT-PCR, Transwell assay, Dye transfer assay
|
Deheng Li et al
|
2020
|
(243)
|
|
|
|
|
|
|
|
|
|
|
|
ZFPM2-AS1
|
Up
|
JMJD6
|
qRT-PCR, Luciferase reporter Assay, Transwell Assay
|
Y-F ZHAO et al
|
2020
|
(244)
|
|
H19
|
Up
|
Let‑7/Lin28
|
qRT-PCR,Wound healing assay, Migration and invasion assays
|
Hanchu Xiong et al
|
2020
|
(197)
|
|
HOST2
|
Up
|
Let-7b
|
qRT-PCR, Dual-luciferase reporter assay, Transwell assay
|
Kaiyao Hua et al
|
2020
|
(26)
|
|
LINC00689
|
Up
|
miR-142-3p/USP6NL
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assays
|
Teng ma et al
|
2020
|
(245)
|
|
AFAP1-AS1
|
Up
|
miR-145/MTH1
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Xiaohui Zhang et al
|
2020
|
(220)
|
|
LINC00511
|
Up
|
miR-150/MMP13
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
GuangHui Shi et al
|
2020
|
(246)
|
|
SNHG3
|
Up
|
miR-154-3p/Notch2
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assay
|
Hongnan Jiang et al
|
2020
|
(247)
|
|
TUSC8
|
Down
|
miR-190b-5p/MYLIP
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Luqing Zhao et al
|
2020
|
(248)
|
|
SNHG1
|
Up
|
miR-193a-5p-HOXA1
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Jun Li et al
|
2020
|
(249)
|
|
H19
|
Up
|
miR-340-3p/YWHAZ
|
qRT‐PCR, Dual‐luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Lei Yan et al
|
2020
|
(198)
|
|
PCNAP1
|
Up
|
miR‑340‑5p/SOX4
|
qRT-PCR, Luciferase reporter assay, Scratch assays, Transwell assays
|
Yang Yu et al
|
2020
|
(250)
|
|
OIP5‑AS1
|
Up
|
miR‑340‑5p/ZEB2
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Lingjun Meng et al
|
2020
|
(251)
|
|
LINC02163
|
Up
|
miR-511-3p/HMGA2
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Chenglin Qin et al
|
2020
|
(252)
|
|
LINC00115
|
Up
|
miR-7/KLF4
|
qRT-PCR, Dual-luciferase reporter assay, Transwell assay, Matrigel invasion assay
|
Chunlei Yuan et al
|
2020
|
(253)
|
|
DCST1-AS1
|
Up
|
miR-873-5p
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell assay
|
Li Tang et al
|
2020
|
(254)
|
|
DANCR
|
Up
|
miR-874-3p/SOX2
|
qRT‐PCR, Dual‐luciferase reporter assay,Transwell Invasion Assay
|
Guiyun Wu et al
|
2020
|
(255)
|
|
|
|
|
|
|
|
|
|
TRHDE‑AS1
|
Down
|
NA
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
Shufang Hu et al
|
2020
|
(256)
|
|
LINC00665
|
Up
|
NA
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
J-L Zhou et al
|
2020
|
(257)
|
|
A2M-AS1
|
Up
|
NA
|
qRT-PCR, Wound-healing assay, Transwell migration and invasion assay
|
Kai Fang et al
|
2020
|
(258)
|
|
DGCR5
|
Up
|
NA
|
qRT-PCR, Transwell invasion assay
|
Daqing Jiang et al
|
2020
|
(190)
|
|
LINC00261
|
Down
|
NME1
|
qRT-PCR, RNA pull-down assay, Transwell Migration Assay
|
Guangxiu Guo et al
|
2020
|
(259)
|
|
H19
|
Up
|
p53/TNFAIP8
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assay
|
Yang Li et al
|
2020
|
(195)
|
|
Linc00514
|
Up
|
STAT3
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Sifeng Tao et al
|
2020
|
(260)
|
|
PHACTR2-AS1 (PAS1)
|
Down
|
SUV39H1
|
qRT‐PCR, Dual‐luciferase reporter assay
|
Wenhui Chu et al
|
2020
|
(261)
|
|
LINC01271
|
UP
|
Tensin1
|
qRT-PCR, Wound healing assay, Migration and invasion assay
|
Kung-Chi Chang et al
|
2020
|
(262)
|
|
RAB11B-AS1
|
Up
|
VEGFA, ANGPTL4
|
qRT-PCR, Luciferase reporter assay, Boyden chamber migration and invasion assays, In vitro angiogenesis assay
|
Yanling Niu et al
|
2020
|
(263)
|
|
HUMT
|
Up
|
YBX1/FOXK1
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
Shaoquan Zheng et al
|
2020
|
(264)
|
|
NNT-AS1
|
Up
|
ZFP36
|
qRT-PCR, Wound healing assay, Transwell assay, Bioinformatics analysis
|
Pan QH et al
|
2020
|
(265)
|
|
LINC00518
|
Up
|
CDX2
|
qRT-PCR, Dual-luciferase reporter assay, Transwell assay, Scratch test
|
Hong-Bin Wang et al
|
2019
|
(201)
|
|
Lnc-NLIPMT (RP11–115N4.1)
|
Down
|
GSK3β
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
Yang Jiang et al
|
2019
|
(266)
|
|
MIR503HG
|
Down
|
miR‐103/OLFM4
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Jia Fu et al
|
2019
|
(267)
|
|
NEAT1
|
Up
|
miR-107/CPT1A
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Matrigel assay
|
Yiquan Xiong et al
|
2019
|
(206)
|
|
|
|
|
|
|
|
|
|
MIR210HG
|
UP
|
miR-1226-3p/mucin-1c
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Xiao-Yu Li et al
|
2019
|
(268)
|
|
NEAT1
|
UP
|
miR-133b/TIMM17A
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Xinping Li et al
|
2019
|
(207)
|
|
AC073284.4
|
Down
|
miR-18b‐5p/DOCK4
|
qRT‐PCR, Dual‐luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Yue‐Yue Wang et al
|
2019
|
(269)
|
|
LINC00641
|
Down
|
miR‐194‐5p
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Qixin Mao et al
|
2019
|
(270)
|
|
LncCCAT1
|
Up
|
miR-204/211, miR-148a/152, ANXA2
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Tingting Tang et al
|
2019
|
(200)
|
|
LncRNA-CDC6
|
Up
|
miR‐215/CDC6
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Xiaoli Kong et al
|
2019
|
(271)
|
|
HCP5
|
UP
|
miR‐219a‐5p/BIRC3
|
qRT‐PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Lihong Wang et al
|
2019
|
(272)
|
|
GAS6-AS2
|
Up
|
miR-493/FUT4
|
qRT‐PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Wanfeng Li et al
|
2019
|
(273)
|
|
LINC00473
|
Up
|
miR-497
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
J BAI et al
|
2019
|
(274)
|
|
LOXL1-AS1
|
UP
|
miR-708-5p
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Hui-ting Dong et al
|
2019
|
(275)
|
|
TFAP2A-AS1
|
Down
|
miR-933/SMAD2
|
qRT‐PCR, Dual‐luciferase reporter assay, Transwell invasion assay
|
Bin Zhou et al
|
2019
|
(276)
|
|
LINC01287
|
Up
|
NA
|
qRT-PCR, Wound healing assay, Transwell invasion assay
|
C. Song et al
|
2019
|
(192)
|
|
AFAP1-AS1
|
Up
|
NA
|
qRT-PCR, Wound scratch assay
|
Dachang Ma et al
|
2019
|
(219)
|
|
LINC01089
|
Down
|
NA
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
Hongfan Yuan et al
|
2019
|
(204)
|
|
RUSC1-AS-N
|
UP
|
NA
|
qRT-PCR, Wound healing assay, Transwell assay
|
Peng Zhou et al
|
2019
|
(193)
|
|
CASC2
|
Down
|
NA
|
qRT-PCR, Transwell migration and invasion assay
|
Yang Zhang et al
|
2019
|
(186)
|
|
|
|
|
|
|
|
|
|
FOXD3‐AS1
|
Up
|
NA
|
qRT-PCR, Invasion and migration assay
|
Yaoyao Guan et al
|
2019
|
(277)
|
|
PANDAR
|
UP
|
NA
|
qRT-PCR, Transwell invasion assay
|
Yi Li et al
|
2019
|
(278)
|
|
HIF1A‐AS2
|
Up
|
NA
|
qRT‐PCR, Transwell migration and invasion assay
|
Yufei Wang et al et al
|
2019
|
(279)
|
|
HOTTIP
|
Up
|
NA
|
qRT-PCR, Wound healing assay, Transwell invasion assay
|
Sijia Han et al
|
2019
|
(194)
|
|
NAMPT-AS
|
UP
|
NAMP
|
qRT‐PCR, Dual‐luciferase reporter assay, Transwell migration and invasion assay
|
Hanwen Zhang et al
|
2019
|
(280)
|
|
Lnc-SLC4A1-1
|
UP
|
NF-kB/CXCL8
|
qRT-PCR, Transwell migration and invasion assay
|
Tongbo Yi et al
|
2019
|
(281)
|
|
ST8SIA6-AS1
|
UP
|
p38 , AKT1
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
Kai Fang et al
|
2019
|
(282)
|
|
FBXL19-AS1
|
Up
|
WDR66
|
qRT‐PCR, RIP assay, Transwell migration and invasion assay
|
Yayuan Zhang et al
|
2019
|
(283)
|
|
ZEB2-AS1
|
Up
|
ZEB2
|
qRT-PCR, Wound healing assay, Transwell assay, Cellular F‐actin measurement
|
Guoxin Zhang et al
|
2019
|
(284)
|
|
TROJAN
|
UP
|
ZMYND8
|
qRT-PCR, Transwell migration and invasion assay
|
Xi Jin et al
|
2019
|
(285)
|
|
LINC01638
|
Up
|
DNMT1, DNMT3a, DNMT3b, BRCA1, PTEN
|
qRT-PCR, Transwell invasion assay
|
Peng Liu et al
|
2018
|
(286)
|
|
ZFHX4-AS1
|
UP
|
FAT4
|
qRT‐PCR, Dual‐luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Shao-Ying Li et al
|
2018
|
(287)
|
|
IRAIN
|
Down
|
IGF1R
|
qRT-PCR, Transwell migration and invasion assay
|
Lingling Pian et al
|
2018
|
(288)
|
|
LncRNA-BCHE (p10247)
|
UP
|
ITGB1
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
Yu-Xia Yang et al
|
2018
|
(289)
|
|
ITGB2-AS1
|
Up
|
ITGB2
|
qRT-PCR, Wound healing assay, Transwell invasion assay
|
Mengyao Liu et al
|
2018
|
(290)
|
|
LncRNA-CTD-2108O9.1
|
Down
|
LIFR
|
qRT-PCR, Wound healing assay, Transwell assay, Matrigel invasion assay
|
Mozhi Wang et al
|
2018
|
(291)
|
|
|
|
|
|
|
|
|
|
NNT-AS1
|
Up
|
miR-142-3p/ZEB1
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Yan Li et al
|
2018
|
(292)
|
|
MALAT1
|
Up
|
miR-145, VEGF
|
qRT-PCR, Transwell migration assay
|
Xiao-juan Huang et al
|
2018
|
(293)
|
|
XIST
|
Down
|
miR-155/CDX1
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Ruinian Zheng et al
|
2018
|
(294)
|
|
SNHG7
|
Up
|
miR-186
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assay
|
X Luo et al
|
2018
|
(295)
|
|
GAS5
|
Down
|
miR-196a-5p/FOXO1/PI3K/AKT
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Shuqin Li et al
|
2018
|
(296)
|
|
LncATB
|
Up
|
miR-200c/Twist1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Rong-Hui Li et al
|
2018
|
(181)
|
|
ARNILA
|
Up
|
miR-204/Sox4
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Fang Yang et al
|
2018
|
(297)
|
|
Lnc015192
|
Up
|
miR-34a/Adam12
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Xiaojia Huang et al
|
2018
|
(298)
|
|
LncRNA-PRLB
|
UP
|
miR-4766-5p/SIRT1
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Yiran Liang et al
|
2018
|
(299)
|
|
XIST
|
Down
|
miR-503, MSN
|
qRT-PCR
|
Fei Xing et al
|
2018
|
(300)
|
|
linc-ZNF469-3
|
Up
|
miR-574-5p/ZEB1
|
qRT-PCR, Luciferase reporter assay, Migration and invasion assays
|
Po-Shun Wang et al
|
2018
|
(301)
|
|
CASC2
|
Down
|
miR-96-5p/SYVN1
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Zejun Gao et al
|
2018
|
(185)
|
|
BANCR
|
Up
|
NA
|
qRT-PCR, Transwell migration and invasion assay
|
Jing Jiang et al
|
2018
|
(302)
|
|
BANCR
|
Up
|
NA
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
K-X Lou et al
|
2018
|
(303)
|
|
EZR-AS1
|
Up
|
NA
|
qRT‐PCR, Transwell migration and invasion assay
|
Yu Bai et al
|
2018
|
(191)
|
|
LINC01296
|
Up
|
NA
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
Min Jiang et al
|
2018
|
(304)
|
|
|
|
|
|
|
|
|
|
AC026904.1, UCA1
|
Up
|
Slug
|
qRT-PCR, Luciferase reporter assay, Transwell migration assay
|
Guo-Yin Li et al
|
2018
|
(183)
|
|
MALAT1
|
Down
|
TEAD
|
qRT-PCR, Luciferase reporter assay
|
Jongchan Kim et al
|
2018
|
(214)
|
|
HOXA-AS2
|
Up
|
miR-520c-3p /TGFBR2 and RELA
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Yu Fang et al
|
2017
|
(305)
|
|
NEAT1
|
UP
|
FOXN3-NEAT1-SIN3A
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Wanjin Li et al
|
2017
|
(205)
|
|
Lnc-BM
|
Up
|
JAK2
|
qRT-PCR, Cell adhesion assay, Trans-BBB invasion assay, Macrophage Transwell migration assay
|
Shouyu Wang et al
|
2017
|
(306)
|
|
MALAT1
|
UP
|
miR-129-5p
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Yonggang Zuo et al
|
2017
|
(212)
|
|
H19
|
Up
|
miR-200b/c and let-7b,Git2,Cyth3
|
qRT‐PCR, Transwell invasion assay
|
Wu Zhou et al
|
2017
|
(196)
|
|
MALAT1
|
Up
|
miR-204/ZEB2
|
qRT-PCR, Luciferase reporter assay, Transwell assays
|
Yuzhou Wang et al
|
2017
|
(307)
|
|
NEAT1
|
Up
|
miR-211/HMGA2
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Xuerui Li et al
|
2017
|
(208)
|
|
SNHG15
|
UP
|
miR-211-3p
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Qingli Kong et al
|
2017
|
(308)
|
|
MEG3
|
Down
|
miR-421/E-cadherin
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assays
|
Wei Zhang et al
|
2017
|
(309)
|
|
MEG3
|
Down
|
NA
|
qRT-PCR, Transwell invasion assay
|
Chen-yu Zhang et al
|
2017
|
(310)
|
|
Linc-ITGB1
|
Down
|
NA
|
qRT-PCR
|
W-X Li et al
|
2017
|
(311)
|
|
LINC00628
|
Down
|
NA
|
qRT-PCR, Transwell migration and invasion assay
|
D-Q Chen et al
|
2017
|
(312)
|
|
OR3A4
|
Up
|
NA
|
qRT-PCR, Transwell migration and invasion assay
|
Genxiang Liu et al
|
2017
|
(313)
|
|
HOXA11‑AS
|
Up
|
NA
|
qRT-PCR, Wound healing assay, Transwell invasion assay
|
Jian-Chun Su et al
|
2017
|
(314)
|
|
|
|
|
|
|
|
|
|
TUG1
|
Down
|
NA
|
qRT-PCR, Transwell migration and invasion assay
|
Shulin Fan et al
|
2017
|
(315)
|
|
HOXA11-AS
|
Up
|
NA
|
qRT-PCR, Wound healing assay, Transwell invasion assay
|
Wenlei Li et al
|
2017
|
(316)
|
|
LincRNA-ROR
|
Up
|
NA
|
qRT-PCR
|
Kaijiong Zhang et al
|
2017
|
(317)
|
|
LincIN
|
Up
|
NF90-p21
|
qRT-PCR, RIP, Wound healing assay, Transwell invasion assay
|
Zhengyu Jiang et al
|
2017
|
(318)
|
|
Linc00617
|
Up
|
Sox2
|
qRT-PCR, RIP, Wound healing assay, Transwell invasion assay
|
Hengyu Li et al
|
2017
|
(319)
|
|
CCAT2
|
Up
|
TGFB1,SMAD2,α-SMA
|
qRT-PCR, transwell assay
|
Z-J WU et al
|
2017
|
(184)
|
|
LINP1
|
Up
|
TP53
|
qRT-PCR, Wound healing assay, Transwell migration and invasion assay
|
Yiran Liang et al
|
2017
|
(320)
|
|
ROR1-HER3 MAYA (MNX1-AS1)
|
Up
|
YAP
|
qRT-PCR, RIP, Transwell migration and invasion assay
|
Chunlai Li et al
|
2017
|
(321)
|
|
ANCR
|
Down
|
EZH2/CDK1
|
qRT-PCR, Wound healing assay, RIP assay, Transwell migration and invasion assay
|
Zhongwei Li et al
|
2016
|
(322)
|
|
LIMT (LINC01089)
|
Down
|
NA
|
qRT-PCR, Transwell migration and invasion assay
|
Aldema Sas-Chen et al
|
2016
|
(323)
|
|
MALAT1
|
Up
|
NA
|
qRT-PCR, Transwell migration and invasion assay
|
Mahdieh Jadaliha et al
|
2016
|
(300)
|
|
MEG3
|
Down
|
NA
|
qRT-PCR
|
J-J ZHANG et al
|
2016
|
(324)
|
|
TUG1
|
Up
|
NA
|
qRT-PCR, Transwell migration and invasion assay
|
Teng Li et al
|
2016
|
(300)
|
|
MALAT1
|
Up
|
NA
|
qRT-PCR, Transwell assay
|
Yufeng Miao et al
|
2016
|
(211)
|
|
MALAT1
|
UP
|
miR-1/cdc42
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Jinjiang Chou et al
|
2016
|
(116)
|
|
HIT
|
Up
|
E-cadherin
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Edward J Richards et al
|
2015
|
(182)
|
|
|
|
|
|
|
|
|
|
NKILA
|
Down
|
IkB
|
qRT-PCR, Luciferase reporter assay
|
Bodu Liu et al
|
2015
|
(325)
|
|
MALAT1
|
Up
|
miR-1/Slug
|
qRT-PCR, Dual-luciferase reporter assay, Transwell invasion assay
|
Chuan Jin et al
|
2015
|
(117)
|
|
LincRNA-ROR
|
Up
|
miR-145/Arf6
|
qRT-PCR, Luciferase reporter assay, Transwell invasion assay
|
Gabriel Eades et al
|
2015
|
(215)
|
|
H19
|
Up
|
miR-675/c-Cbl, Cbl-b
|
qRT‐PCR, Luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Constance Vennin et al
|
2015
|
(326)
|
|
EGOT
|
Down
|
NA
|
qRT-PCR
|
Shou-ping Xu et al
|
2015
|
(327)
|
|
MALAT1
|
Down
|
NA
|
qRT–PCR, Wound healing assay, Matrigel invasion assay
|
Shouping Xu et al
|
2015
|
(210)
|
|
NBAT1
|
Down
|
PRC2, DKK1
|
qRT-PCR, RIP, Wound healing assay, Transwell migration and invasion assay
|
Pengnan Hu et al
|
2015
|
(328)
|
|
LINC-ROR
|
Up
|
miR-205 / ZEB2
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
P Hou et al
|
2014
|
(216)
|
|
BCAR4
|
Up
|
PNUTS, SNIP1
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assay
|
Zhen Xing et al
|
2014
|
(329)
|
|
HOTAIR
|
-
|
NA
|
qRT-PCR
|
Cleidson Pádua Alves et al
|
2013
|
(217)
|
|
CCAT2
|
Up
|
NA
|
qRT-PCR, Transwell migration assay
|
Roxana S Redis et al
|
2013
|
(330)
|
|
HOTAIR
|
Up
|
NA
|
Breast Tissue Microarrays, ISH
|
Karen M Chisholm et al
|
2012
|
(331)
|
3.3.4 The role of CircRNAs in Breast Cancer Metastasis:
Circular RNAs, a unique category of long noncoding RNAs, have a covalently closed loop structure without a 5′-cap or 3′-polyadenylated tail (332). This special structure enables them to express themselves well and be more stable than their counterparts (333). According to research, the development of BCM may be aided by circRNAs competing with other endogenous RNAs to bind to MREs or miRNAs, RNA-binding proteins (RBPs), or regulating parental genes (333). As a result, they can control downstream gene expression and modulate the essential biological processes of tumor progression and metastasis (334). By controlling different genes or signaling networks, they can either prevent or promote BC migration, invasion, and metastasis (334,335). Fig. 9 depicts the mechanisms of circRNA-mediated regulation in BCM.
The inhibitory effects of circRNAs on BC invasion and metastasis were shown in multiple investigations. For instance, circEHMT1 can act as a tumor suppressor in BC by targeting miR-1233-3p, modifying the transcription factor KLF4, and then MMP2; it may be able to prevent invasion, migration and metastasis in a particular axis of circEHMT1/miR-1233-3p/KLF4/MMP2 (336). In metastatic BC, circNR3C2 upregulates and sponges miR-513a-3p, which can enhance the tumor-suppressive effects of HRD1 that modulate vimentin, a vital regulator of EMT (337). CircRGPD6 can also inhibit metastatic BCSCs through the miR-26b/YAF2 axis, and TV-circRGPD6 nanoparticles, either alone or in combination with docetaxel, demonstrated notable therapeutic responses on metastatic BCSCs (338). Moreover, circNOL10 not only can bind multiple miRNAs such as miR-149-5p, miR-330-3p, and miR-452-5p to alleviate BC carcinogenesis by regulating PDCD4 but also can act as an RBP-noncoding RNA and CASC3 and MTDH proteins bind directly to it with characterized motifs and inhibit BCM (339). CircNOL10 was represented in another study as a suppressor of BCM via sponging miR-767-5p and up-regulating SOCS2, which inactivates the JAK2/STAT5 signaling pathway (340). According to Liang Y et al., circBMPR2 down regulated in BCM. Additionally, sponging miR-553 by this circRNA results in overexpression of USP4, a TSG, inhibiting the metastasis and tamoxifen resistance (341). Further, it is reported that the Yap protein, a vital Hippo pathway component, can be inhibited by its circular RNA (circYap) and attenuate BC migration and invasion (342).
Regarding the upregulation of circRNAs in BCM, it has been revealed that overexpression of circ-UBR1 could lead to BCM via miR-1299/CCND1 axis (343). In TNBC, circRAD18 sponges miR-208a and miR-3164 and increased IGF1 and FGF2 expression were associated with poor prognosis and distant metastasis, as well as cell migration and invasion in BC cell lines (344). Furthermore, it has been demonstrated that TNBC metastasis and progression could be facilitated via circ-UBAP2/ miR-661/MTA1 (345), circSEPT9/miR-637/LIF (27) and circIFI30/miR-520b-3p/CD44 axis (346). In the positive feedback loop of circHIF1A/NFIB/FUS (347), circHIF1A can be overexpressed and accelerate TNBC metastasis and invasion (347). CircDNAJC11 can directly regulate TAF15/MAPK6 and activate the MAPK signaling pathway in TNBC (348). CircANKS1B through miR-148a-3p and miR-152-3p/ USF1/ TGF-β1 activates TGF-β1/Smad signaling and promotes EMT (349). Li Y et al. found that circ-EIF6, which encodes EIF6-224aa, may be responsible for TNBC invasion and progression by inhibiting the MYH9 oncogene degradation and activation of the Wnt/β-catenin pathway (350).
Besides, CircHIPK3 can assist the progress of BCM by regulating miR-193a/HMGB1 and PI3K/AKT signaling pathways (351). With inhibition of miR-296-5p, hsa_circ_0000515 can overexpress CXCL10 and promote cell invasiveness in the MCF-7 cell line and nude mice (352). Gao D et al. indicate that circ_0006528 up-regulated in BCM and sponges miR-7-5p to overexpressed Raf1, ultimately in the way activated MAPK/ERK signaling pathway (353). Further, Ju CH et al. introduced a novel circRNA, circ_0042881, which in a ceRNA-network sponges' miR-217, affects SOS1 and activates MEK/ERK pathway and PI3K/AKT pathway (354). They also claim that EIF4A3 could facilitate circ_0042881 circularization in this axis (354). In addition, it has been shown that circMYBL2 upregulated in BC liver metastasis and sponging miR-1205, then complexing with eIF4A3 and promoting EMT, or it can directly target eIF4A3 through circMYBL2/eIF4A3/ E2F1 axes and leads to BC liver metastasis (355). Several other studies had been reported the upregulation of circRNAs and sponging miRNAs in a particular axis can enhance or facilitate BCM including CircKIF4A/ miR-152/ZEB1 (356), circFOXK2/ IGF2BP3/miR-370 (357), circ_0072995/ SHMT2/miR-149-5p (358), circFBXL5/miR‐660/ SRSF6 (359), circHMCU/ let-7/ MCY/HMGA2/CCND1 (360), circIRAK3/miR-3607/FOXC1 (361), circACAP2/ miR-29a/b-3p-COL5A1 (362), circ_0000291/miR-326/ETS1 axes (363). Table. 4 comprehensively represents circRNAs and their targets, which play a role in BCM progression.
Table. 4. List of circRNAs and their targets, which are involved in the BCM.
|
CircRNA
|
Regulation
|
Target
|
Detection Method(s)
|
Authors
|
Year
|
Title
|
|
circKIF4A
|
Up
|
miR-637/STAT3
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Song Wu et al
|
2024
|
(364)
|
|
circRNF10
|
Down
|
DHX15
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell assay
|
Wenfang Zheng et al
|
2023
|
(365)
|
|
circ_0060467 (circMYBL2)
|
Up
|
miR-1205/E2F1 and eIF4A3/E2F1
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Yan Zeng et al
|
2023
|
(355)
|
|
circ_0042881
|
Up
|
miR-217/SOS1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration assay
|
Chenxi Ju et al
|
2023
|
(354)
|
|
circDNAJC11
|
Up
|
TAF15/MAPK6
|
qRT-PCR, RIP, Transwell migration and invasion assay
|
Bin Wang et al
|
2023
|
(348)
|
|
circ-EIF6
|
Up
|
MYH9
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Yaming Li et al
|
2022
|
(350)
|
|
circFOXK2
|
Up
|
IGF2BP3/miR-370
|
qRT-PCR, Luciferase reporter assay, Migration and invasion assay
|
Wei Zhang et al
|
2021
|
(357)
|
|
circRASSF2
|
Up
|
miR-1205/HOXA1
|
qRT-PCR, Dual-luciferase reporter assay, Transwell assay
|
Wei Zhong et al
|
2021
|
(366)
|
|
circ-ERBB2
|
Up
|
miR-136-5p/TFAP2C or miR-198/TFAP2C
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assays
|
Jin-xiu Zhong
|
2021
|
(367)
|
|
circHIF1A
|
Up
|
miR-149-5p/NFIB/FUS
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell assay
|
Tong Chen et al
|
2021
|
(347)
|
|
circ_0000515
|
Up
|
miR-296-5p/CXCL10
|
qRT-PCR, Dual-luciferase reporter assay, Transwell assay
|
Fenglin Cai et al
|
2021
|
(352)
|
|
circNR3C2
|
Down
|
miR-513a-3p/HRD1/Vimentin
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Matrigel invasion assay
|
Ya Fan et al
|
2021
|
(337)
|
|
circNOL10
|
Down
|
miR-767-5p/SOCS2/JAK2/STAT5
|
qRT-PCR, Dual-luciferase reporter Assay, Transwell Assay
|
Fang Wang et al
|
2021
|
(340)
|
|
circHMCU
|
Up
|
let-7/MCY/HMGA2/CCND1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Xiaojin Song et al
|
2020
|
(360)
|
|
circEHMT1
|
Down
|
miR-1233-3p/KLF4/MMP2
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Mengqi Lu et al
|
2020
|
(336)
|
|
circ_0091074
|
Down
|
miR-1297/TAZ/TEAD4
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay
|
Jiashu Hu et al
|
2020
|
(368)
|
|
circ-UBR1
|
Up
|
miR-1299/CCND1
|
qRT‐PCR, Dual‐luciferase reporter assay, Transwell migration and invasion assay
|
Linfeng Zhang et al
|
2020
|
(343)
|
|
circVAPA
|
Up
|
miR-130a-5p
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Si-ying Zhou et al
|
2020
|
(369)
|
|
circ-NOL10
|
Down
|
miR-149-5p/miR-330-3p/miR-452-5p/PDCD4
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Matrigel invasion assay
|
Yujie Cai et al
|
2020
|
(339)
|
|
circ_0072995
|
Up
|
miR-149-5p/SHMT2
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assay, Cell adhesion assay
|
Chuang Qi et al
|
2020
|
(358)
|
|
circKIF4A
|
Up
|
miR-152/ZEB1
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assay
|
Yongping Jin et al
|
2020
|
(356)
|
|
circHIPK3
|
Up
|
miR-193a/HMGB1/PI3K/AKT
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell invasion assay
|
Zhen-Gang Chen et al
|
2020
|
(351)
|
|
circRGPD6
|
Down
|
miR-26b-YAF2
|
qRT-PCR
|
Xiaoti Lin et al
|
2020
|
(338)
|
|
circACAP2
|
Up
|
miR-29a/miR-29b-3p/COL5A1
|
qRT-PCR, Luciferase reporter assay, Transwell migration and invasion assays
|
Beiyong Zhao et al
|
2020
|
(362)
|
|
circ_0000291
|
Up
|
miR‐326/ETS1
|
qRT-PCR, Dual-luciferase reporter assay, Transwell assay
|
Jie Min et al
|
2020
|
(363)
|
|
circIFI30
|
Up
|
miR-520b-3p/CD44
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing and invasion assays
|
Lei Xing et al
|
2020
|
(346)
|
|
circSEPT9
|
Up
|
miR-637/LIF
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assays
|
Xiaying Zheng et al
|
2020
|
(27)
|
|
circFBXL5
|
Up
|
miR‐660/SRSF6
|
Microarray, Luciferase reporter assay
|
Huamao Zhou et al
|
2020
|
(359)
|
|
circSCYL2
|
Down
|
NA
|
qRT-PCR, Transwell migration and invasion assay
|
Chunlei Yuan et al
|
2020
|
(370)
|
|
circRNA_0025202
|
Down
|
miR-182-5p/FOXO3a
|
qRT-PCR, Luciferase reporter assay, Transwell migration assay
|
Yuting Sang et al
|
2019
|
(371)
|
|
circDENND4C
|
Up
|
miR-200b/c
|
qRT-PCR, Luciferase reporter assay,3D spheroid invasion assay, Transwell migration and invasion assay
|
Shasha Ren et al
|
2019
|
(372)
|
|
circRAD18
|
Up
|
miR-208a/3164-IGF1/FGF2
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell assay
|
Yutian Zou et al
|
2019
|
(344)
|
|
circAHNAK1
|
Down
|
miR-421/RASA1
|
qRT-PCR, Luciferase reporter assay,Transwell assay, Migration assay
|
Weikai Xiao et al
|
2019
|
(373)
|
|
circASS1
|
Down
|
miR-4443
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Jun-chen Hou et al
|
2019
|
(374)
|
|
circKDM4C
|
Down
|
miR-548p/PBLD
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Yiran Liang et al
|
2019
|
(375)
|
|
circBMPR2
|
Down
|
miR-553/USP4
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Yiran Liang et al
|
2019
|
(341)
|
|
circ-21439, circ-11783
|
circ 21439 Up
circ 11783 Down
|
NA
|
qRT-PCR
|
Xiaorong Lin et al
|
2019
|
(376)
|
|
circYap
|
Down
|
Yap
|
qRT-PCR, RIP, Wound healing assay, Transwell invasion assay
|
Nan Wu et al
|
2019
|
(342)
|
|
CiRS-7
|
Up
|
miR-1299/MMP
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Meixiang Sang et al
|
2018
|
(25)
|
|
circANKS1B
|
Up
|
miR-148a-3p/152-3p/USF1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell assays
|
Kaixuan Zeng et al
|
2018
|
(349)
|
|
circ-0072995
|
Up
|
miR-30c-2-3p
|
qRT-PCR, Dual-luciferase reporter assay, Transwell migration and invasion assays
|
He-da Zhang et al
|
2018
|
(377)
|
|
circIRAK3
|
Up
|
miR-3607/FOXC1
|
qRT-PCR, Luciferase reporter assay, Wound healing assay, Transwell assay
|
Jie Wu et al
|
2018
|
(361)
|
|
circ-UBAP2
|
Up
|
miR-661/MTA1
|
qRT-PCR, Luciferase reporter assay, Transwell migration assay
|
Shengting Wang et al
|
2018
|
(345)
|
|
circRNA_0006528
|
Up
|
miR-7-5p/Raf1/MEK/ERK
|
qRT-PCR, Dual-luciferase reporter assay, Wound healing assay, Transwell migration and invasion assay
|
Danfeng Gao et al
|
2018
|
(353)
|
|
FECR1
|
Up
|
TET1 and DNMT1
|
qRT-PCR, RNA reverse transcription-associated trap (RAT), Matrigel invasion assay
|
Naifei Chen et al
|
2018
|
(378)
|
|
circ_0001785
|
Up
|
NA
|
qRT-PCR
|
Wei-Bing Yin et al
|
2017
|
(379)
|
3.3.5 CeRNA physiology and participation in BC metastasis regulation:
The term "competing endogenous RNAs" (ceRNAs) describes RNA transcripts, including circular RNAs, ncRNAs such as circRNAs and lncRNAs, pseudogene transcripts, and mRNAs, that have the ability to control one another by engaging in competition for the binding to MicoRNA Response Elements (MREs) (20,380,381). Based on the ceRNA hypothesis, the miRNA Sponge is integrated into the RNA-induced silencing complex and binds to its target mRNAs to modify the expression of the target (382). RNA editing, RNA-binding proteins, miRNA/ceRNA abundance, and ceRNAs' affinity for miRNAs are some variables that affect ceRNA activity (382) (Fig. 10). Any of these changes could result in an imbalance in the ceRNA-network, which would aid in the development and metastasis of BC (16,22). Recent research on BC has shown that the characteristics of BCM development are largely determined by the dysregulation of many ceRNA-networks (383). Furthermore, it is believed that such a finding would provide a fresh perspective on the concealed facets. Despite the intricacy of the process, ceRNA regulatory networks that impact several metastasis parameters may be responsible for the frequent metastatic progression of BC (23).
As a result, the study of ceRNA-networks in metastasis has gained a special interest because most ceRNAs, including lncRNAs and circRNAs, have been found to contribute negatively to BC by influencing EMT, migration, invasion, and metastasis (24,384,385). Other ceRNAs associated with EMT in BC include HOTAIR, HULC, and NEAT1, all promoting a mesenchymal phenotype (214,386,387). The miR-200 family and p53 gene regulation regulate EMT, controlling mesenchymal transcription factors (307,388). Other ceRNAs associated with EMT in BC include HOTAIR, HULC, and NEAT1, all promoting a mesenchymal phenotype (389). The miR-200 family and p53 gene regulation regulate EMT, controlling mesenchymal transcription factors (298,390).
The ongoing validation of ceRNA theory has provided new insights into BCM and invasion, leading to the discovery of therapeutic targets and biomarkers and enhancing clinical efficacy and prognosis. Nevertheless, due to the great diversity of BCM-related ceRNAs and their intricate ceRNA networks and inadequate experimental validation, there is a lack of systematic organization and comprehensive assessment of BC-related ceRNAs.