Time resolved gene expression analysis during tamoxifen adaption of MCF-7 cells identifies long non-coding RNAs with prognostic impact

被引:7
|
作者
Porsch, Martin [1 ,2 ,3 ]
Ozdemir, Esra [4 ]
Wisniewski, Martin [4 ]
Graf, Sebastian [1 ]
Bull, Fabian [1 ,2 ,3 ]
Hoffmann, Katrin [2 ]
Ignatov, Atanas [5 ]
Haybaeck, Johannes [4 ,6 ,7 ]
Grosse, Ivo [1 ,3 ]
Kalinski, Thomas [4 ]
Nass, Norbert [4 ]
机构
[1] Martin Luther Univ Halle Wittenberg, Insitute Comp Sci, Halle, Germany
[2] Martin Luther Univ Halle Wittenberg, Inst Human Genet, Halle, Germany
[3] German Ctr Integrat Biodivers Res iDiv, Leipzig, Germany
[4] Otto von Guericke Univ, Inst Pathol, Leipziger Str 44, D-39120 Magdeburg, Germany
[5] Otto von Guericke Univ, Dept Obstet & Gynecol, Magdeburg, Germany
[6] Med Univ Graz, Diagnost & Res Inst Pathol, Diagnost & Res Ctr Mol BioMed, Graz, Austria
[7] Med Univ Innsbruck, Dept Pathol, Innsbruck, Austria
关键词
Breast cancer; tamoxifen; long-non coding RNAs; biomarker; gene expression; ESTROGEN-RECEPTOR-ALPHA; BREAST-CANCER; OXIDATIVE-STRESS; RESISTANCE; MEMBRANE; VARIANT; GPR30; ER-ALPHA-36; MECHANISMS; THERAPY;
D O I
10.1080/15476286.2019.1581597
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Acquired tamoxifen resistance is a persistent problem for the treatment of estrogen receptor positive, premenopausal breast cancer patients and predictive biomarkers are still elusive. We here analyzed gene expression changes in a cellular model to identify early and late changes upon tamoxifen exposure and thereby novel prognostic biomarkers. Estrogen receptor positive MCF-7 cells were incubated with 4OH-tamoxifen (10 nM) and gene expression analyzed by array hybridization during 12 weeks. Array results were confirmed by nCounter- and qRT-PCR technique. Pathway enrichment analysis revealed that early responses concerned mainly amine synthesis and NRF2-related signaling and evolved into a stable gene expression pattern within 4 weeks characterized by changes in glucuronidation-, estrogen metabolism-, nuclear receptor- and interferon signaling pathways. As a large number of long non coding RNAs was subject to regulation, we investigated 5 of these (linc01213, linc00632 linc0992, LOC101929547 and XR_133213) in more detail. From these, only linc01213 was upregulated but all were less abundant in estrogen-receptor negative cell lines (MDA-MB 231, SKBR-3 and UACC3199). In a web-based survival analysis linc01213 and linc00632 turned out to have prognostic impact. Linc01213 was investigated further by plasmid-mediated over-expression as well as siRNA down-regulation in MCF-7 cells. Nevertheless, this had no effect on proliferation or expression of tamoxifen regulated genes, but migration was increased. In conclusion, the cellular model identified a set of lincRNAs with prognostic relevance for breast cancer. One of these, linc01213 although regulated by 4OH-tamoxifen, is not a central regulator of tamoxifen adaption, but interferes with the regulation of migration.
引用
收藏
页码:661 / 674
页数:14
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