lncRNA 多态性与中国人群乳腺癌易感性。

Polymorphisms in lncRNA and susceptibility to breast cancer in Chinese population.

机构信息

Department of Gastroenterology and Hepatology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Jinshui, Zhengzhou 450003, Henan, China.

Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China.

出版信息

Aging (Albany NY). 2021 Nov 11;13(21):24360-24378. doi: 10.18632/aging.203686.

DOI:10.18632/aging.203686

PMID:34762068

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8610136/

Abstract

BACKGROUND

Published studies based on pharmacokinetics have explored the relationship between the lncRNA and the prognosis of breast cancer (BC) resistance and recurrence. However, the underlying association of SNPs with BC development remains unclear.

METHODS

Combining bioinformatics and databases, SNPs (Single Nucleotide Polymorphisms) in the gene were screened, and SNPs in the lncRNA were selected for genotyping among 504 Chinese Han patients and 505 healthy controls, which were frequency-matched for age (±2 years). Logistic regression analysis was used to explore the association between SNPs and the BC risk. Interactions between the SNPs and reproductive factors were further evaluated using the multifactor dimensionality reduction (MDR) method. qRT-PCR was performed to detect expression in individuals with different genotypes of rs34841297. The target miRNA, miR-4456 of rs34841297 was predicted by websites and confirmed by performing dual luciferase gene reporter assays. CCK-8 and Transwell experiments were designed to explore the effects of miR-4456 on the proliferation, invasion and migration of BC cells.

RESULTS

In this study, nine SNPs were screened. After adjusting for age, menarche age, menopausal status, number of pregnancies, history of abortions, breast feeding history and family history of BC, the results of the logistic regression analysis showed the rs34841297 A/- gene polymorphism was positively correlated with the incidence of BC. Compared with the AA genotype, patients with the A-+-- genotype of rs34841297 at age<50 years, and menarche age<14 years, Premenopausal status, history of abortion, no history of breastfeeding and no family history of tumors in first-degree relatives had an increased risk of BC. MDR results revealed that individuals with rs34841297 - (homozygous deletion) of the A allele who were not menopausal and had no history of breastfeeding had a higher risk of BC. qRT-PCR results revealed that homozygous deletion (1.68±1.37) of the rs34841297 A- genotype resulted in higher expression than the heterozygous deletion genotype (0.95±0.94) and wild AA genotype (0.26±0.12). Binding between and miR-4456 was occurred when rs34841297 carried the AA genotype. Moreover, preliminary functional studies indicated that the overexpression of miR-4456 increased the proliferation, invasion and migration of BC cells.

CONCLUSION

Our study showed that the gene polymorphism may be related to BC susceptibility, and the rs34841297 A/- genotype may probably affect the proliferation, invasion and migration of BC cells by modulating the interactions with of miR-4456.

摘要

背景

基于药代动力学的已发表研究探讨了长非编码 RNA（lncRNA）与乳腺癌（BC）耐药和复发的预后之间的关系。然而，SNP 与 BC 发展的潜在关联仍不清楚。

方法

结合生物信息学和数据库，筛选基因中的 SNP，在 504 例中国汉族患者和 505 例健康对照者中选择 lncRNA 中的 SNP 进行基因分型，年龄（±2 岁）频率匹配。使用 logistic 回归分析探讨 SNP 与 BC 风险的关系。进一步使用多因素维度降低（MDR）方法评估 SNP 与生殖因素之间的相互作用。对不同 rs34841297 基因型个体的表达进行 qRT-PCR 检测。通过网站预测 rs34841297 的靶 miRNA，miR-4456，并通过双荧光素酶基因报告基因检测进行验证。设计 CCK-8 和 Transwell 实验，探讨 miR-4456 对 BC 细胞增殖、侵袭和迁移的影响。

结果

本研究共筛选出 9 个 SNP。在调整年龄、初潮年龄、绝经状态、妊娠次数、流产史、母乳喂养史和 BC 家族史后，logistic 回归分析结果表明 rs34841297 A/- 基因多态性与 BC 的发病呈正相关。与 AA 基因型相比，rs34841297 A-+-- 基因型、年龄<50 岁、初潮年龄<14 岁、绝经前状态、流产史、无母乳喂养史和一级亲属无肿瘤家族史的患者发生 BC 的风险增加。MDR 结果显示，A 等位基因纯合缺失（rs34841297-）且未绝经且无母乳喂养史的个体发生 BC 的风险更高。qRT-PCR 结果显示，rs34841297 A- 基因型的纯合缺失（1.68±1.37）导致的表达高于杂合缺失基因型（0.95±0.94）和野生 AA 基因型（0.26±0.12）。当 rs34841297 携带 AA 基因型时，与 miR-4456 发生结合。此外，初步功能研究表明，miR-4456 的过表达增加了 BC 细胞的增殖、侵袭和迁移。