Triple-Negative Breast Cancer circRNAome Reveals Hsa_circ_0072309 as a Potential Risk Biomarker
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Ethics Approval and Consent to Participate
2.2. TNBC Sample Series, RNA-Seq Data, circRNA and mRNA Mapping, and Data Analysis
2.3. CircRNA-RBP Prediction
2.4. Functional Enrichment Analysis
2.5. Biological Samples
2.6. Total RNA Isolation and RT-qPCR
2.7. Statistical Analysis
3. Results
3.1. CircRNAs and Their Host Genes Are Predominantly Downregulated in TNBC
3.2. CircRNAs Interact with RNA Binding Proteins and Enrich to Cancer-Related Pathways
3.3. TNBC Patients with BRCA1 Mutations Have a Distinct circRNA Profile When Compared to Wildtype Ones
3.4. Hsa_circ_0072309 Is a Potential Biomarker of TNBC and May Be Involved in Cancer-Related Gene Regulation Signaling
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinical Characteristics | Wildtype | Wildtype, BRCA Hypermethylated | BRCA1 Mutation | |||
---|---|---|---|---|---|---|
n = 18 | n = 10 | p-Value * | n = 9 | p-Value * | ||
Age of onset, mean (SD) | 41.8 (6.1) | 38.5 (7.6) | 0.3 | 36.5 (5.6) | 0.16 | |
nº (%) | nº (%) | nº (%) | ||||
TNM classification, T | T1 | 3 (16.7) | - | 0.11 | 1 (11.1) | 0.94 |
T2 | 8 (44.4) | 9 (90) | 5 (55.6) | |||
T3 | 3 (16.7) | 1 (10) | 2 (22.2) | |||
T4 | 4 (22.2) | - | 1 (11.1) | |||
TNM classification, N | N0 | 5 (27.8) | 8 (80) | 0.054 | 5 (55.6) | 0.59 |
N1 | 7 (38.9) | 2 (20) | 3 (33.3) | |||
N2 | 4 (22.2) | 1 (11.1) | ||||
N3 | 2 (11.1) | - | ||||
TNM classification, M | M0 | 11 (61.1) | 8 (80) | 0.41 | 4 (44.4) | 0.06 |
M1 | 7 (38.9) | 2 (20) | 2 (22.2) | |||
Mx | - | - | 3 (33.3) | |||
Tumor stage | I | 2 (11.1) | - | 0.07 | 1 (11.1) | 0.45 |
II | 7 (38.9) | 9 (90) | 5 (55.6) | |||
III | 7 (38.9) | 1 (10) | 1 (11.1) | |||
IV | 2 (11.1) | - | - | |||
Tumor grade | 2 | 4 (22.2) | - | 0.26 | - | 0.056 |
3 | 14 (77.8) | 10 (100) | 7 (77.8) | |||
Chemotherapy | No | 11 (61.1) | 8 (80) | 0.5 | 6 (66.7) | 0.65 |
Yes | 4 (22.2) | 2 (20) | 3 (33.3) | |||
TP53 mutation | No | 4 (22.2) | - | 0.13 | 4 (44.4) | 1 |
Yes | 12 (66.7) | 6 (60) | 5 (55.6) | |||
Family history | No | 10 (55.6) | 5 (50) | 0.87 | 2 (22.2) | 0.001 |
Yes | 2 (11.1) | 2 (20) | 7 (77.8) | |||
Outcome | ||||||
Relapse or metastasis | No | 11 (61.1) | 5 (50) | 0.69 | 7 (77.8) | 1 |
Yes | 7 (38.9) | 5 (50) | 2 (22.2) | |||
Death | No | 13 (72.2) | 7 (70) | 1 | 7 (77.8) | 1 |
Yes | 5 (27.8) | 3 (30) | 2 (22.2) |
Host Gene | Strand | circRNA | BaseMean | Log2FC | Padj |
---|---|---|---|---|---|
LIFR | − | hsa_circ_0072309 | 7.478 | −2.392 | 4.68 × 10−11 |
SEMA3C | − | hsa_circ_0004365 | 5.284 | −2.347 | 6.61 × 10−10 |
MIR31HG | − | hsa_circ_0008599 | 3.758 | −1.981 | 3.61 × 10−06 |
EXOC6B | − | hsa_circ_0009043 | 10.768 | −1.955 | 2.74 × 10−07 |
WDR78 | − | hsa_circ_0006677 | 8.343 | −1.931 | 1.29 × 10−07 |
FAM126A | − | hsa_circ_0008951 | 4.761 | −1.925 | 2.74 × 10−07 |
ACVR2A | + | hsa_circ_0001073 | 11.392 | −1.895 | 3.01 × 10−07 |
RMST | + | hsa_circ_0099634 | 3.223 | −1.846 | 8.57 × 10−05 |
N4BP2L2 | − | hsa_circ_0000471 | 24.928 | −1.825 | 3.61 × 10−06 |
RHOBTB3 | + | hsa_circ_0007444 | 8.915 | −1.700 | 1.66 × 10−04 |
SEMA3C | − | hsa_circ_0002714 | 2.767 | −1.693 | 2.00 × 10−04 |
FGFR1 | − | hsa_circ_0008016 | 2.983 | −1.641 | 3.11 × 10−04 |
RBM23 | − | hsa_circ_0000524 | 7.974 | −1.626 | 8.57 × 10−05 |
PRDM5 | − | hsa_circ_0005654 | 2.864 | −1.584 | 5.28 × 10−04 |
NFIB | − | hsa_circ_0086376 | 7.423 | −1.540 | 2.00 × 10−04 |
TPTEP1 | + | chr22:17117929-17119630 | 5.560 | −1.522 | 2.76 × 10−03 |
EPSTI1 | − | hsa_circ_0000479 * | 4.422 | 1.560 | 2.55 × 10−04 |
circRNAs | RBP | Number of circRNAs Binding Sites * | RBP Function | Reference |
---|---|---|---|---|
hsa_circ_0009043 | AGO1 | 1 | miRNA-mediated gene regulation | [35] |
hsa_circ_0072309, hsa_circ_0009043, hsa_circ_0004365, hsa_circ_0000479 | AGO2 | 3/1/6/1 | miRNA-mediated gene regulation | [35] |
hsa_circ_0072309, hsa_circ_0009043, hsa_circ_0004365, hsa_circ_0008599, hsa_circ_0006677 | EIF4A3 | 6/4/6/1/2 | RNA splicing by acting as a core component of the spliceosome and splicing-dependent exon junction complex | [36] |
hsa_circ_0072309, hsa_circ_0009043, hsa_circ_0004365 | ELAVL1 (HuR) | 2/2/2 | Increase mRNA stability through binding to their 3’-UTR | [37] |
hsa_circ_0072309 | EWSR1 | 4 | Regulating transcription through interaction with CREB-binding protein; RNA splicing by cooperating with multiple splicing factors | [38,39] |
hsa_circ_0072309 | FMR1 (FMRP) | 3 | Associates in an RNA-dependent manner with MOV10 and facilitates miRNA-mediated gene silencing; binds to mRNAs and mediates RNA transport from nucleus to cytoplasm | [40,41] |
hsa_circ_0072309 | FUS | 1 | Mediates the binding of U1 snRNP and RNAPII, being required for splicing to occur during transcription | [42] |
hsa_circ_0072309, hsa_circ_0004365 | IGF2BP1 | 1/1 | Binding to cytoplasmic mRNAs in order to prevent premature RNA decay; transport RNA in the cytoplasm and provide stability to bound mRNAs | [43,44,45] |
hsa_circ_0072309, hsa_circ_0004365 | IGF2BP2 | 1/1 | Binding to cytoplasmic mRNAs in order to prevent premature RNA decay; transport RNA in the cytoplasm and provide stability to bound mRNAs | [43,44,45] |
hsa_circ_0072309, hsa_circ_0004365 | IGF2BP3 | 1/2 | Binding to cytoplasmic mRNAs in order to prevent premature RNA decay; transport RNA in the cytoplasm and provide stability to bound mRNAs | [43,44,45] |
hsa_circ_0072309 | LIN28A | 2 | Stimulates translation by actively recruiting RNA helicase A to polysomes; inhibiting miRNA biogenesis | [46,47] |
hsa_circ_0072309 | LIN28B | 1 | Stimulates translation by actively recruiting RNA helicase A to polysomes; inhibiting miRNA biogenesis | [46,47] |
hsa_circ_0072309, hsa_circ_0009043, hsa_circ_0004365 | PTBP1 | 1/1/3 | Exon exclusion during alternative splicing events and mRNA stabilization; stimulates translation at picorna virus internal ribosome entry sites (IRES) | [48,49] |
hsa_circ_0072309 | U2AF2 (U2AF) | 1 | Activation of splicing and its coupling to transcription; 3’ end processing of vertebrates | [50,51] |
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Magalhães, L.; Ribeiro-dos-Santos, A.M.; Cruz, R.L.; Nakamura, K.D.d.M.; Brianese, R.; Burbano, R.; Ferreira, S.P.; Oliveira, E.L.F.d.; Anaissi, A.K.M.; Nahúm, M.C.d.S.; et al. Triple-Negative Breast Cancer circRNAome Reveals Hsa_circ_0072309 as a Potential Risk Biomarker. Cancers 2022, 14, 3280. https://doi.org/10.3390/cancers14133280
Magalhães L, Ribeiro-dos-Santos AM, Cruz RL, Nakamura KDdM, Brianese R, Burbano R, Ferreira SP, Oliveira ELFd, Anaissi AKM, Nahúm MCdS, et al. Triple-Negative Breast Cancer circRNAome Reveals Hsa_circ_0072309 as a Potential Risk Biomarker. Cancers. 2022; 14(13):3280. https://doi.org/10.3390/cancers14133280
Chicago/Turabian StyleMagalhães, Leandro, André M. Ribeiro-dos-Santos, Rebecca L. Cruz, Kivvi Duarte de Mello Nakamura, Rafael Brianese, Rommel Burbano, Sâmio Pimentel Ferreira, Ewaldo Lúcio Foro de Oliveira, Ana Karyssa Mendes Anaissi, Márcia Cristina de Sousa Nahúm, and et al. 2022. "Triple-Negative Breast Cancer circRNAome Reveals Hsa_circ_0072309 as a Potential Risk Biomarker" Cancers 14, no. 13: 3280. https://doi.org/10.3390/cancers14133280