Assessment of Non-Coding RNAs (miR-506 and circRNA 000284) and their Target Gene SNAIL-2 in Breast Tumors: Implications for Prognosis and a Possible Circulating Biomarker
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Abstract
Breast cancer is the most common malignancy among women, and early diagnosis and targeted therapy have garnered significant attention. Non-coding RNAs have emerged as potential diagnostic, prognostic, and treatment biomarkers for breast cancer. This study aimed to evaluate the expression of non-coding RNAs, specifically miR-506 and circular RNA 000284, and their target gene SNAIL-2 in breast tumors compared to normal controls. The study also focused on clinicopathological characteristics, and plasma was monitored for expression of circ0000284 to identify a possible accessible cancer-related marker. Using the SYBR-Green Real-time PCR technique, total RNA was extracted from 80 breast tumors and normal adjacent tissues, and circ0000284, miR-506, and SNAIL2 expression were analyzed. The results showed overexpression, down-regulation, and up-regulation of circRNA 000284, miR-506, and SNAIL-2 gene, respectively. These expression changes were associated with advanced stages of the disease and lymph nodal involvement, which are signs of a poor prognosis. Additionally, a positive direct correlation was observed between circRNA000284 expression in tumors and plasma. Moreover, it was discovered that circ-0000284 sponged miR-506, causing up-regulation of SNAIL-2 as its mRNA target. The upregulation of SNAIL-2 as an epithelial-mesenchymal-transition (EMT)factor leads to poor prognosis in breast cancer and is epigenetically regulated by miR-506 and circRNA 000284. Therefore, the overexpression of circRNA000284 in plasma could be considered an indicator of lymph nodal involvement and advanced stages of cancer, and nominated as a poor prognostic biomarker for future considerations.
1. Harbeck N, Gnant M. Breast cancer. The Lancet. 2017; 389: 1134-1150. doi: 10.1016/S0140-6736(16)31891-8.
2. Farhood B, Geraily G, Alizadeh A. Incidence and Mortality of Various Cancers in Iran and Compare to Other Countries: A Review Article. Iran J Public Health. 2018; 47: 309-316.
3. Nafissi N, Khayamzadeh M, Zeinali Z, Pazooki D, Hosseini M , Akbari ME. Epidemiology and Histopathology of Breast Cancer in Iran versus Other Middle Eastern Countries. Middle East Journal of Cancer. 2018; 9: 243-251. doi: 10.30476/mejc.2018.42130
4. Deans C, Maggert KA. What do you mean, "epigenetic"? Genetics. 2015; 199: 887-96. doi: 10.1534/genetics.114.173492
5. Wang G, Wang B, Yang P. Epigenetics in Congenital Heart Disease. J Am Heart Assoc. 2022;11:e025163. doi: 10.1161/JAHA.121.025163.
6. Sanger Hl, Klotz G, Riesner D, Gross HJ, Kleinschmidt AK. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci U S A. 1976;73:3852-6. doi: 10.1073/pnas.73.11.3852.
7. Kolakofsky D. Isolation and characterization of Sendai virus DI-RNAs. Cell 1976; 8: 547-55. doi: 10.1016/0092-8674(76)90223-3.
8. Cocquerelle C, Mascrez B, Hétuin D, Bailleul B. Mis-splicing yields circular RNA molecules. FASEB J. 1993;7:155-60. doi: 10.1096/fasebj.7.1.7678559.
9. Su M, Xiao Y, Ma J, Tang Y, Tian B, Zhang Y, et al. Circular RNAs in Cancer: emerging functions in hallmarks, stemness, resistance and roles as potential biomarkers. Mol Cancer. 2019;18:90. doi: 10.1186/s12943-019-1002-6.
10. Zhao X, Zhong Y, Wang X, Shen J, An W. Advances in Circular RNA and Its Applications. Int J Med Sci 2022; 19: 975-985. doi: 10.7150/ijms.71840.
11. Beilerli A, Gareev I, Beylerli O, Yang G, Pavlov V, Aliev G, et al. Circular RNAs as biomarkers and therapeutic targets in cancer. Semin Cancer Biol. 2022;83:242-252. doi: 10.1016/j.semcancer.2020.12.026.
12. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013; 495:384-8. doi: 10.1038/nature11993. Epub 2013 Feb 27. PMID: 23446346.
13. Rybak-Wolf A, Stottmeister C, Glažar P, Jens M, Pino N, Giusti S, et al. Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. Mol Cell. 2015; 58:870-85. doi: 10.1016/j.molcel.2015.03.027.
14. Salzman J, Chen Re, Olsen MN, Wang PL, Brown PO. Cell-type specific features of circular RNA expression. PLoS Genet 2013; 9:e1003777. doi: 10.1371/journal.pgen.
15. Lee Rc, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843-54. doi: 10.1016/0092-8674(93)90529-y.
16. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002; 99:15524-9. doi: 10.1073/pnas.242606799.
17.Van Meter EN, Onyango JA, Teske KA. A review of currently identified small molecule modulators of microRNA function. Eur J Med Chem. 2020; 188:112008. doi: 10.1016/j.ejmech.2019.112008.
18. Kehl T, Backes C, Kern F, Fehlmann T, Ludwig N, Meese E. About miRNAs, miRNA seeds, target genes and target pathways. Oncotarget. 2017; 8:107167-107175. doi: 10.18632/oncotarget.22363.
19. Huang G, Li S, Yang N, Zou Y, Zheng D, Xiao T. Recent progress in circular RNAs in human cancers. Cancer Lett. 2017; 404:8-18. doi: 10.1016/j.canlet.2017.07.002.
20. Huang J, Zhou Q, Li Y. Circular RNAs in gynecological disease: promising biomarkers and diagnostic targets. Biosci Rep. 2019; 39:BSR20181641. doi: 10.1042/BSR20181641.
21. Ma HB, Yao YN, Yu JJ, Chen XX, Li HF. Extensive profiling of circular RNAs and the potential regulatory role of circRNA-000284 in cell proliferation and invasion of cervical cancer via sponging miR-506. Am J Transl Res. 2018; 10:592-604. PMID: 29511454; PMCID: PMC5835825.
22. Waks AG, Winer EP. Breast Cancer Treatment: A Review. JAMA. 2019; 321:288-300. doi: 10.1001/jama.2018.19323.
23. Zheng Q, Bao C, Guo W, Li S, Chen J, Chen B. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun 2016; 7:11215. doi: 10.1038/ncomms11215.
24. Zeng K, Chen X, Xu M, Liu X, Hu X, Xu T, et al. CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7. Cell Death Dis. 2018; 9:417. doi: 10.1038/s41419-018-0454-8.
25. Li Y, Zheng F, Xiao X, Xie F, Tao D, Huang C, et al. CircHIPK3 sponges miR-558 to suppress heparanase expression in bladder cancer cells. EMBO Rep. 2017; 18:1646-1659. doi: 10.15252/embr.201643581. Epub 2017 Aug 9. Erratum in: EMBO Rep. 2022 Nov 7;23(11):e56102.
26. Cai C, Zhi Y, Wang K, Zhang P, Ji Z, Xie C, et al. CircHIPK3 overexpression accelerates the proliferation and invasion of prostate cancer cells through regulating miRNA-338-3p. Onco Targets Ther 2019; 12:3363-3372. doi: 10.2147/OTT.S196931.
2. Farhood B, Geraily G, Alizadeh A. Incidence and Mortality of Various Cancers in Iran and Compare to Other Countries: A Review Article. Iran J Public Health. 2018; 47: 309-316.
3. Nafissi N, Khayamzadeh M, Zeinali Z, Pazooki D, Hosseini M , Akbari ME. Epidemiology and Histopathology of Breast Cancer in Iran versus Other Middle Eastern Countries. Middle East Journal of Cancer. 2018; 9: 243-251. doi: 10.30476/mejc.2018.42130
4. Deans C, Maggert KA. What do you mean, "epigenetic"? Genetics. 2015; 199: 887-96. doi: 10.1534/genetics.114.173492
5. Wang G, Wang B, Yang P. Epigenetics in Congenital Heart Disease. J Am Heart Assoc. 2022;11:e025163. doi: 10.1161/JAHA.121.025163.
6. Sanger Hl, Klotz G, Riesner D, Gross HJ, Kleinschmidt AK. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci U S A. 1976;73:3852-6. doi: 10.1073/pnas.73.11.3852.
7. Kolakofsky D. Isolation and characterization of Sendai virus DI-RNAs. Cell 1976; 8: 547-55. doi: 10.1016/0092-8674(76)90223-3.
8. Cocquerelle C, Mascrez B, Hétuin D, Bailleul B. Mis-splicing yields circular RNA molecules. FASEB J. 1993;7:155-60. doi: 10.1096/fasebj.7.1.7678559.
9. Su M, Xiao Y, Ma J, Tang Y, Tian B, Zhang Y, et al. Circular RNAs in Cancer: emerging functions in hallmarks, stemness, resistance and roles as potential biomarkers. Mol Cancer. 2019;18:90. doi: 10.1186/s12943-019-1002-6.
10. Zhao X, Zhong Y, Wang X, Shen J, An W. Advances in Circular RNA and Its Applications. Int J Med Sci 2022; 19: 975-985. doi: 10.7150/ijms.71840.
11. Beilerli A, Gareev I, Beylerli O, Yang G, Pavlov V, Aliev G, et al. Circular RNAs as biomarkers and therapeutic targets in cancer. Semin Cancer Biol. 2022;83:242-252. doi: 10.1016/j.semcancer.2020.12.026.
12. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013; 495:384-8. doi: 10.1038/nature11993. Epub 2013 Feb 27. PMID: 23446346.
13. Rybak-Wolf A, Stottmeister C, Glažar P, Jens M, Pino N, Giusti S, et al. Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. Mol Cell. 2015; 58:870-85. doi: 10.1016/j.molcel.2015.03.027.
14. Salzman J, Chen Re, Olsen MN, Wang PL, Brown PO. Cell-type specific features of circular RNA expression. PLoS Genet 2013; 9:e1003777. doi: 10.1371/journal.pgen.
15. Lee Rc, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843-54. doi: 10.1016/0092-8674(93)90529-y.
16. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002; 99:15524-9. doi: 10.1073/pnas.242606799.
17.Van Meter EN, Onyango JA, Teske KA. A review of currently identified small molecule modulators of microRNA function. Eur J Med Chem. 2020; 188:112008. doi: 10.1016/j.ejmech.2019.112008.
18. Kehl T, Backes C, Kern F, Fehlmann T, Ludwig N, Meese E. About miRNAs, miRNA seeds, target genes and target pathways. Oncotarget. 2017; 8:107167-107175. doi: 10.18632/oncotarget.22363.
19. Huang G, Li S, Yang N, Zou Y, Zheng D, Xiao T. Recent progress in circular RNAs in human cancers. Cancer Lett. 2017; 404:8-18. doi: 10.1016/j.canlet.2017.07.002.
20. Huang J, Zhou Q, Li Y. Circular RNAs in gynecological disease: promising biomarkers and diagnostic targets. Biosci Rep. 2019; 39:BSR20181641. doi: 10.1042/BSR20181641.
21. Ma HB, Yao YN, Yu JJ, Chen XX, Li HF. Extensive profiling of circular RNAs and the potential regulatory role of circRNA-000284 in cell proliferation and invasion of cervical cancer via sponging miR-506. Am J Transl Res. 2018; 10:592-604. PMID: 29511454; PMCID: PMC5835825.
22. Waks AG, Winer EP. Breast Cancer Treatment: A Review. JAMA. 2019; 321:288-300. doi: 10.1001/jama.2018.19323.
23. Zheng Q, Bao C, Guo W, Li S, Chen J, Chen B. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun 2016; 7:11215. doi: 10.1038/ncomms11215.
24. Zeng K, Chen X, Xu M, Liu X, Hu X, Xu T, et al. CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7. Cell Death Dis. 2018; 9:417. doi: 10.1038/s41419-018-0454-8.
25. Li Y, Zheng F, Xiao X, Xie F, Tao D, Huang C, et al. CircHIPK3 sponges miR-558 to suppress heparanase expression in bladder cancer cells. EMBO Rep. 2017; 18:1646-1659. doi: 10.15252/embr.201643581. Epub 2017 Aug 9. Erratum in: EMBO Rep. 2022 Nov 7;23(11):e56102.
26. Cai C, Zhi Y, Wang K, Zhang P, Ji Z, Xie C, et al. CircHIPK3 overexpression accelerates the proliferation and invasion of prostate cancer cells through regulating miRNA-338-3p. Onco Targets Ther 2019; 12:3363-3372. doi: 10.2147/OTT.S196931.
| Files | ||
| Issue | Vol 15 No 2 (2023) | |
| Section | Original Articles | |
| Keywords | ||
| breast cancer circRNA000284 miR-506 noncoding RNAs prognostic biomarker | ||
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How to Cite
1.
Salimi M, Dashti Gohari S. Assessment of Non-Coding RNAs (miR-506 and circRNA 000284) and their Target Gene SNAIL-2 in Breast Tumors: Implications for Prognosis and a Possible Circulating Biomarker. Basic Clin Cancer Res. 2024;15(2):81-93.
