Volkogon A. D., Obukhova O. A., Harbuzova V. Yu., Ataman A. V.

MEDICAL GENETICS

Scentific article

HOX antisense intergenic RNA (HOTAIR), the well-studied long noncoding RNA (lnRNA), realizes the regulation of cell cycle genes expression at the epigenetic and transcriptional levels. The results of experiments showed that HOTAIR promotes epithelial-mesenchymal transition (EMT) during the renal-cell carcinoma (RCC) development. Moreover, HOTAIR knockdown inhibits proliferation and invasion of RCC cells. At the same time the role of HOTAIR gene polymorphisms in kidney cancer development is unknown. The aim of the study was to perform a case-control study on representatives of both genders in order to assess the possible link between HOTAIR rs1899663 gene polymorphism and kidney cancer development in Ukrainian population. Object and methods. 141 unrelated Ukrainian patients (42 female, 59 male) with clear cell renal cell carcinoma (CCRCC) and 100 healthy subjects (34 female, 56 male) were enrolled to case-control study. HOTAIR rs1899663 polymorphism genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). The mathematical processing of obtained results was done using Statistical Package for Social Science software (SPSS, version 17.0, Chicago, IL, USA). All statistical tests were two-sided, P <0.05 was considered significant. Results. It was shown that ratio of HOTAIR rs1899663 GG-, GT- and TT-genotypes between CCRCC patients and control subjects did not differ (P = 0.207). Comparison of rs1899663 genotype frequencies in groups of different sex demonstrated no significant difference between CCRCC patients and control group in women (P = 0.067) and men (P = 0.248). The results of logistic regression analysis showed the association between HOTAIR rs1899663 polymorphic locus and CCRCC occurrence in female subjects under superdominant model of inheritance. Women with GT-genotype had 2.7 times increased risk of kidney cancer development compared to women with GG- and TTgenotypes (95% СІ = 1.058-6.868; Р = 0.038). The link between HOTAIR rs1899663 gene polymorphism and CCRCC development in male subjects was not found in any inheritance model (P > 0.05). Conclusion. Obtained results revealed that long non-coding RNA HOTAIR rs1899663 polymorphic site was associated with kidney cancer development only in female Ukrainian patients. The risk of CCRCC occurrence in women with GT-genotype was higher than in women with GG- and TT-genotypes.

long non-coding RNA, HOTAIR, gene polymorphism, kidney cancer

1. Li M, Wang Y, Song Y, Bu R, Yin B, Fei X, et al. Expression profiling and clinicopathological significance of DNA methyltransferase 1, 3A and 3B in sporadic human renal cell carcinoma. Int J Clin Exp Pathol. 2014;7(11):7597-609.
2. Mosashvilli D, Kahl P, Mertens C, Holzapfel S, Rogenhofer S, Hauser S, et al. Global histone acetylation levels: prognostic relevance in patients with renal cell. Cancer Sci. 2010;101(12):2664-9.
3. Li M, Wang Y, Cheng L, Niu W, Zhao G, Raju JK, et al. Long non-coding RNAs in renal cell carcinoma: A systematic review and clinical implications. Oncotarget. 2017;8(29):48424-35.
4.  Liu H, Chen P, Jiang C, Han J, Zhao B, Ma Y, et al. Screening for the Key lncRNA Targets Associated With Metastasis of Renal Clear Cell Carcinoma. Medicine (Baltimore). 2016;95(2):e2507.
5. Blondeau JJ, Deng M, Syring I, Schrödter S, Schmidt D, Perner S. Identification of novel long non-coding RNAs in clear cell renal cell carcinoma. Clin Epigenetics. 2015;7:10.
6. Yu X, Li Z. Long non-coding RNA HOTAIR: A novel oncogene (Review). Mol Med Rep. 2015;12(4):5611-8. DOI: 10.3892/mmr.2015.4161
7. Lee M, Kim HJ, Kim SW, Park SA, Chun KH, Cho NH, et al. The long non-coding RNA HOTAIR increases tumour growth and invasion in cervical cancer by targeting the Notch pathway. Oncotarget. 2016;7(28):44558-71.
8. Wu Y, Liu J, Zheng Y, You L, Kuang D, Liu T. Suppressed expression of long non-coding RNA HOTAIR inhibits proliferation and tumourigenicity of renal carcinoma cells. Tumour Biol. 2014;35(12):11887-94.
9.  Yan R, Cao J, Song C, Chen Y, Wu Z, Wang K, et al. Polymorphisms in lncRNA HOTAIR and susceptibility to breast cancer in a Chinese population. Cancer Epidemiol. 2015;39(6):978-85.
10. Li H, Tang XM, Liu Y, Li W, Chen Q, Pan Y. Association of Functional Genetic Variants of HOTAIR with Hepatocellular Carcinoma (HCC) Susceptibility in a Chinese Population. Cell Physiol Biochem. 2017;44(2):447-54.
11.  Taheri M, Habibi M, Noroozi R, Rakhshan A, Sarrafzadeh S, Sayad A, et al. HOTAIR genetic variants are associated with prostate cancer and benign prostate hyperplasia in an Iranian population. Gene. 2017;613:20-4.
12. Gong WJ, Yin JY, Li XP, Fang C, Xiao D, Zhang W, et al. Association of well-characterized lung cancer lncRNA polymorphisms with lung cancer susceptibility and platinum-based chemotherapy response. Tumour Biol. 2016;37(6):8349-58.
13.  Sanchez DJ, Steger DJ, Skuli N, Bansal A, Simon MC. PPARγ is dispensable for clear cell renal cell carcinoma progression. Mol Metab. 2018;139- 49.
14.  Lucas B, Grigo K, Erdmann S, Lausen J, Klein-Hitpass L, Ryffel GU. HNF4a reduces proliferation of kidney cells and affects genes deregulated in renal cell carcinoma. Oncogene. 2005;24(42):6418-31.
15. Hassanzarei S, Hashemi M, Sattarifard H, Hashemi SM, Bahari G, Ghavami S. Genetic polymorphisms of HOTAIR gene are associated with the risk of breast cancer in a sample of southeast Iranian population. Tumour Biol. 2017;39(10):1010428317727539. DOI: 10.1177/1010428317727539
16. Weng SL, Wu WJ, Hsiao YH, Yang SF, Hsu CF, Wang PH. Significant association of long non-coding RNAs HOTAIR genetic polymorphisms with cancer recurrence and patient survival in patients with uterine cervical cancer. Int J Med Sci. 2018;15(12):1312-9.
17. Guo L, Lu X, Zheng L, Liu X, Hu M. Association of Long Non-Coding RNA HOTAIR Polymorphisms with Cervical Cancer Risk in a Chinese Population. PLoS One. 2016;e0160039.

«Bulletin of problems biology and medicine» Issue 1 Part 2 (149), 2019 year, 221-224 pages, index UDK 616.6-006:577.213/.216

10.29254/2077-4214-2019-1-2-149-221-224