Hypermethylation of Long Non-Coding RNA Genes GAS5, Hotair, Hotairm1 and SSTR5-AS1 As Factors in the Development and Progression of Metastatic Breast Cancer

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Metastasis to the lymph nodes is one of the most important factors in the poor prognosis of patients with breast cancer; the five-year survival rate for metastatic breast cancer is less than 30%. DNA methylation occurs in the early stages of the development of cancer, and also plays an important role in the development of lymphatic metastases and can serve as a diagnostic and prognostic marker of malignant tumors, including breast cancer. The lncRNA genes GAS5, HOTAIR, HOTAIRM1, SSTR5-AS1, presumably hypermethylated in breast cancer and associated with epithelial-mesenchymal transition and metastasis, were bioinformatically selected. Quantitative methyl-specific PCR showed a statistically significant increase in the methylation level of these lncRNA genes in breast tumors compared to the paired norm. Hypermethylation of the HOTAIRM1 and SSTR5-AS1 genes in breast cancer was identified for the first time. Using statistical analysis, positive correlations were established between methylation levels for the GAS5-HOTAIR and SSTR5-AS1-HOTAIRM1 pairs. The result of co-methylation of GAS5 and HOTAIR in breast cancer is consistent with the bioinformatically predicted (using enrichment analysis and the ncPath database) participation of these lncRNAs in the regulation of common signaling pathways and biological processes. The level of methylation of the lncRNA genes HOTAIRM1 and SSTR5-AS1 is associated with indicators of breast cancer progression (stage of the tumor process, tumor size, presence of metastases in the lymph nodes). A model has been proposed for assessing the risk of developing lymphogenous metastases depending on the level of methylation of the HOTAIRM1 gene. Thus, data were obtained on lncRNAs GAS5, HOTAIR, HOTAIRM1 and SSTR5-AS1 and hypermethylation of their genes as factors in the development and progression of metastatic breast cancer.

Full Text

Restricted Access

About the authors

E. A. Filippova

Institute of General Pathology and Pathophysiology

Author for correspondence.
Email: p.lenyxa@yandex.ru
Russian Federation, Moscow, 125315

S. S. Lukina

Institute of General Pathology and Pathophysiology

Email: p.lenyxa@yandex.ru
Russian Federation, Moscow, 125315

V. I. Loginov

Institute of General Pathology and Pathophysiology; Medical Genetic Research Center

Email: p.lenyxa@yandex.ru
Russian Federation, Moscow, 125315; Moscow, 115522

A. M. Burdennyy

Institute of General Pathology and Pathophysiology

Email: p.lenyxa@yandex.ru
Russian Federation, Moscow, 125315

I. V. Pronina

Institute of General Pathology and Pathophysiology

Email: p.lenyxa@yandex.ru
Russian Federation, Moscow, 125315

N. A. Arzhanukhina

N.N. Blokhin National Medical Research Center of Oncology, the Ministry of Health of Russia

Email: p.lenyxa@yandex.ru
Russian Federation, Moscow, 115478

T. P. Kazubskaya

N.N. Blokhin National Medical Research Center of Oncology, the Ministry of Health of Russia

Email: p.lenyxa@yandex.ru
Russian Federation, Moscow, 115478

E. A. Braga

Institute of General Pathology and Pathophysiology; Medical Genetic Research Center

Email: p.lenyxa@yandex.ru
Russian Federation, Moscow, 125315; Moscow, 115522

References

  1. Bray F., Laversanne M., Sung H. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries // CA Cancer J. Clin. 2024. doi: 10.3322/caac.21834
  2. Siegel R.L., Miller K.D., Fuchs H.E. et al. Cancer statistics, 2022 // CA Cancer J. Clin. 2022. V. 72. № 1. P. 7–33. doi: 10.3322/caac.21708
  3. To B., Isaac D., Andrechek E.R. Studying lymphatic metastasis in breast cancer: Current models, strategies, and clinical perspectives // J. Mammary Gland Biol. Neoplasia. 2020. V. 25. № 3. P.191–203. doi: 10.1007/s10911-020-09460-5
  4. Kim M.Y. Breast cancer metastasis // Adv. Exp. Med. Biol. 2021. V. 1187. P. 183–204. doi: 10.1007/978-981-32-9620-6_9
  5. Shukla S., Penta D., Mondal P. et al. Epigenetics of breast cancer: Clinical status of epi-drugs and phytochemicals // Adv. Exp. Med. Biol. 2019. V. 1152. P. 293–310. doi: 10.1007/978-3-030-20301-6_16
  6. Rahman M.M., Brane A.C., Tollefsbol T.O. MicroRNAs and epigenetics strategies to reverse breast cancer // Cells. 2019. V. 8. № 10. doi: 10.3390/cells8101214
  7. Cervena K., Siskova A., Buchler T. et al. Methylation-based therapies for colorectal cancer // Cells. 2020. V. 9. № 6. doi: 10.3390/cells9061540
  8. Yan H., Bu P. Non-coding RNA in cancer // Essays Biochem. 2021. V. 65. № 4. P. 625–639. doi: 10.1042/EBC20200032
  9. Ahmadpour S.T., Orre C., Bertevello P.S. et al. Breast cancer chemoresistance: Insights into the regulatory role of lncRNA // Int. J. Mol. Sci. 2023. V. 24. № 21. ID. 15897. doi: 10.3390/ijms242115897
  10. Yang F., Lv S. LncRNA EPB41L4A-AS1 regulates cell proliferation, apoptosis and metastasis in breast cancer // Ann. Clin. Lab. Sci. 2022. V. 52. № 1. P. 3–11. Erratum in: Ann. Clin. Lab. Sci. 2022. V. 52. № 3. ID. 510.
  11. Hashemi M., Moosavi M.S., Abed H.M. et al. Long non-coding RNA (lncRNA) H19 in human cancer: From proliferation and metastasis to therapy // Pharmacol. Res. 2022. V. 184. doi: 10.1016/j.phrs.2022.106418
  12. Kim J., Piao H.L., Kim B.J. et al. Long noncoding RNA MALAT1 suppresses breast cancer metastasis // Nat. Genet. 2018. V. 50. № 12. P. 1705–1715. doi: 10.1038/s41588-018-0252-3
  13. Brierley J.D., Gospodarowicz M.K., Chichester C.W. TNM Classification of Malignant Tumours. 8th. ed. / Eds 2017. 272 p.
  14. World Medical Association. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects // JAMA. 2013. V. 310. № 20. P. 2191–2194. doi: 10.1001/jama.2013.281053
  15. Loginov V.I., Pronina I.V., Filippova E.A. et al. Aberrant methylation of 20 miRNA genes specifically involved in various steps of ovarian carcinoma spread: From primary tumors to peritoneal macroscopic metastases // Int. J. Mol. Sci. 2022. V. 23. № 3. doi: 10.3390/ijms23031300
  16. Wu J., Xiao Y., Xia C. et al. Identification of biomarkers for predicting lymph node metastasis of stomach cancer using clinical DNA methylation data // Dis. Markers. 2017. V. 2017. doi: 10.1155/2017/5745724
  17. Teschendorff A.E., Gao Y., Jones A. et al. DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer // Nat. Commun. 2016. V. 29. № 7. doi: 10.1038/ncomms10478
  18. Lu L., Zhu G., Zhang C. et al. Association of large noncoding RNA HOTAIR expression and its downstream intergenic CpG island methylation with survival in breast cancer // Breast Cancer Res. Treat. 2012. V. 136. № 3. P. 875–83 . doi: 10.1007/s10549-012-2314-z
  19. Selezneva A.D., Filippova E.A., Selezneva A.D. et al. Hypermethylation of long non-coding RNA genes group in the breast cancer development and progression // Bull. Exp. Biol. Med. 2022. V. 173. № 6. P. 765–769. doi: 10.1007/s10517-022-05627-8
  20. Liu W., Zhan J., Zhong R. et al. Upregulation of long noncoding RNA_GAS5 suppresses cell proliferation and metastasis in laryngeal cancer via regulating PI3K/AKT/mTOR signaling pathway // Technol. Cancer Res. Treat. 2021. V. 20. doi: 10.1177/1533033821990074.
  21. Sadeghalvad M., Mansouri K., Mohammadi-Motlagh H.R. et al. Long non-coding RNA HOTAIR induces the PI3K/AKT/mTOR signaling pathway in breast cancer cells // Rev. Assoc. Med. Bras. 2022. V. 68. № 4. P. 456–462. doi: 10.1590/1806-9282.20210966
  22. Yu X., Duan W., Wu F. et al. LncRNA-HOTAIRM1 promotes aerobic glycolysis and proliferation in osteosarcoma via the miR-664b-3p/Rheb/mTOR pathway // Cancer Sci. 2023. V. 114. № 9. P. 3537–3552. doi: 10.1111/cas.15881

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Methylation level of the lncRNA genes GAS5, HOTAIR, HOTAIRM1, SSTR5-AS1 in tumor samples of the mammary gland and in paired norm. T – tumor; N – norm / adjacent histologically normal mammary gland tissue.

Download (402KB)
Indexing metadata
3. Fig. 2. Correlation of the relative methylation level of the HOTAIR and GAS5 lncRNA genes.

Download (242KB)
Indexing metadata
4. Fig. 3. The relationship between the methylation level of the HOTAIRM1 and SSTR5-AS1 lncRNA genes and the stage of the oncological process (a), tumor size (b) and lymphogenous metastasis (c). See text. NO – samples without metastases in the lymph nodes.

Download (229KB)
Indexing metadata

Copyright (c) 2024 Russian Academy of Sciences